Protein kinase C inhibitors and uses thereof

ABSTRACT

This disclosure concerns compounds which are useful as inhibitors of protein kinase C (PKC) and are thus useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of PKC. This disclosure also relates to pharmaceutical compositions that include these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/095,893, filed Dec. 3, 2013, which claims benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 61/733,259, filed Dec. 4,2012, the disclosures of each of which are hereby incorporated herein byreference in their entirety.

INTRODUCTION

Protein kinase C (“PKC”) is a key enzyme in signal transduction involvedin a variety of cellular functions, including cell growth, regulation ofgene expression, and ion channel activity. The PKC family of isozymesincludes at least 11 different protein kinases that can be divided intoat least three subfamilies based on their homology and sensitivity toactivators. Each isozyme includes a number of homologous (“conserved” or“C”) domains interspersed with isozyme-unique (“variable” or “V”)domains. Members of the “classical” or “cPKC” subfamily, PKC α, β_(i),β_(ii) and γ, contain four homologous domains (C1, C2, C3 and C4) andrequire calcium, phosphatidylserine, and diacylglycerol or phorbolesters for activation. Members of the “novel” or “nPKC” subfamily, PKCδ, ϵ, η and θ, lack the C2 homologous domain and do not require calciumfor activation. Finally, members of the “atypical” or “αPKC” subfamily,PKC ζ and λ/i, lack both the C2 and one-half of the C1 homologousdomains and are insensitive to diacylglycerol, phorbol esters andcalcium.

SUMMARY

This disclosure concerns compounds which are useful as inhibitors ofprotein kinase C (PKC) and are thus useful for treating a variety ofdiseases and disorders that are mediated or sustained through theactivity of PKC. This disclosure also relates to pharmaceuticalcompositions that include these compounds, methods of using thesecompounds in the treatment of various diseases and disorders, processesfor preparing these compounds and intermediates useful in theseprocesses.

Embodiments of the chemical structures are provided throughout thedisclosure. By way of example, such compounds are represented by thefollowing formula (I):

wherein

R¹¹ is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy, amino,substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl,aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,sulfide, substituted sulfide, and SF₅;

Y¹ and Y² are independently selected from hydrogen and alkyl; and

Ar¹ is selected from aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;

or a salt or stereoisomer thereof.

DETAILED DESCRIPTION

This disclosure concerns compounds which are useful as inhibitors ofprotein kinase C (PKC) and are thus useful for treating a variety ofdiseases and disorders that are mediated or sustained through theactivity of PKC. This disclosure also relates to pharmaceuticalcompositions that include these compounds, methods of using thesecompounds in the treatment of various diseases and disorders, processesfor preparing these compounds and intermediates useful in theseprocesses.

Before the present invention is further described, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

It must be noted that as used herein and in the appended claims, thesingular forms “a,” “an,” and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is specifically contemplated. The upper and lower limitsof these smaller ranges may independently be included in the smallerranges, and are also encompassed within the invention, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits, ranges excluding either or both ofthose included limits are also included in the invention.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

Except as otherwise noted, the methods and techniques of the presentembodiments are generally performed according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout the presentspecification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, NewYork: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith andMarch, March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, Fifth Edition, Wiley-Interscience, 2001; or Vogel, A Textbookof Practical Organic Chemistry, Including Qualitative Organic Analysis,Fourth Edition, New York: Longman, 1978.

The nomenclature used herein to name the subject compounds isillustrated in the Examples herein. This nomenclature has generally beenderived using the commercially-available AutoNom software (MDL, SanLeandro, Calif.).

Terms

The following terms have the following meanings unless otherwiseindicated. Any undefined terms have their art recognized meanings.

“Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groupshaving from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms.This term includes, by way of example, linear and branched hydrocarbylgroups such as methyl (CH₃—), ethyl (CH₃CH₂—), n-propyl (CH₃CH₂CH₂—),isopropyl ((CH₃)₂CH—), n-butyl (CH₃CH₂CH₂CH₂—), isobutyl ((CH₃)₂CHCH₂—),sec-butyl ((CH₃)(CH₃CH₂)CH—), t-butyl ((CH₃)₃C—), n-pentyl(CH₃CH₂CH₂CH₂CH₂—), and neopentyl ((CH₃)₃CCH₂—).

The term “substituted alkyl” refers to an alkyl group as defined hereinwherein one or more carbon atoms in the alkyl chain have been optionallyreplaced with a heteroatom such as —O—, —N—, —S—, —S(O)_(n)— (where n is0 to 2), —NR— (where R is hydrogen or alkyl) and having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-aryl,—SO₂-heteroaryl, and —NR^(a)R^(b), wherein R′ and R″ may be the same ordifferent and are chosen from hydrogen, optionally substituted alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl andheterocyclic.

“Alkylene” refers to divalent aliphatic hydrocarbyl groups preferablyhaving from 1 to 6 and more preferably 1 to 3 carbon atoms that areeither straight-chained or branched, and which are optionallyinterrupted with one or more groups selected from —O—, —NR¹⁰—,—NR¹⁰C(O)—, —C(O)NR¹⁰— and the like. This term includes, by way ofexample, methylene (—CH₂—), ethylene (—CH₂CH₂—), n-propylene(—CH₂CH₂CH₂—), iso-propylene (—CH₂CH(CH₃)—), (—C(CH₃)₂CH₂CH₂—),(—C(CH₃)₂CH₂C(O)—), (—C(CH₃)₂CH₂C(O)NH—), (—CH(CH₃)CH₂—), and the like.

“Substituted alkylene” refers to an alkylene group having from 1 to 3hydrogens replaced with substituents as described for carbons in thedefinition of “substituted” below.

The term “alkane” refers to alkyl group and alkylene group, as definedherein.

The term “alkylaminoalkyl”, “alkylaminoalkenyl” and “alkylaminoalkynyl”refers to the groups R′NHR″— where R′ is alkyl group as defined hereinand R″ is alkylene, alkenylene or alkynylene group as defined herein.

The term “alkaryl” or “aralkyl” refers to the groups -alkylene-aryl and-substituted alkylene-aryl where alkylene, substituted alkylene and arylare defined herein.

“Alkoxy” refers to the group —O-alkyl, wherein alkyl is as definedherein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the like. Theterm “alkoxy” also refers to the groups alkenyl-O—, cycloalkyl-O—,cycloalkenyl-O—, and alkynyl-O—, where alkenyl, cycloalkyl,cycloalkenyl, and alkynyl are as defined herein.

The term “substituted alkoxy” refers to the groups substituted alkyl-O—,substituted alkenyl-O—, substituted cycloalkyl-O—, substitutedcycloalkenyl-O—, and substituted alkynyl-O— where substituted alkyl,substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyland substituted alkynyl are as defined herein.

The term “alkoxyamino” refers to the group —NH-alkoxy, wherein alkoxy isdefined herein.

The term “haloalkoxy” refers to the groups alkyl-O— wherein one or morehydrogen atoms on the alkyl group have been substituted with a halogroup and include, by way of examples, groups such as trifluoromethoxy,and the like.

The term “haloalkyl” refers to a substituted alkyl group as describedabove, wherein one or more hydrogen atoms on the alkyl group have beensubstituted with a halo group. Examples of such groups include, withoutlimitation, fluoroalkyl groups, such as trifluoromethyl, difluoromethyl,trifluoroethyl and the like.

The term “alkylalkoxy” refers to the groups -alkylene-O-alkyl,alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, andsubstituted alkylene-O-substituted alkyl wherein alkyl, substitutedalkyl, alkylene and substituted alkylene are as defined herein.

The term “alkylthioalkoxy” refers to the group -alkylene-S-alkyl,alkylene-S-substituted alkyl, substituted alkylene-S-alkyl andsubstituted alkylene-S-substituted alkyl wherein alkyl, substitutedalkyl, alkylene and substituted alkylene are as defined herein.

“Alkenyl” refers to straight chain or branched hydrocarbyl groups havingfrom 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and havingat least 1 and preferably from 1 to 2 sites of double bond unsaturation.This term includes, by way of example, bi-vinyl, allyl, andbut-3-en-1-yl. Included within this term are the cis and trans isomersor mixtures of these isomers.

The term “substituted alkenyl” refers to an alkenyl group as definedherein having from 1 to 5 substituents, or from 1 to 3 substituents,selected from alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO— substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

“Alkynyl” refers to straight or branched monovalent hydrocarbyl groupshaving from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms andhaving at least 1 and preferably from 1 to 2 sites of triple bondunsaturation. Examples of such alkynyl groups include acetylenyl(—C≡CH), and propargyl (—CH₂C≡CH).

The term “substituted alkynyl” refers to an alkynyl group as definedherein having from 1 to 5 substituents, or from 1 to 3 substituents,selected from alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO— substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl, and —SO₂-heteroaryl.

“Alkynyloxy” refers to the group —O-alkynyl, wherein alkynyl is asdefined herein. Alkynyloxy includes, by way of example, ethynyloxy,propynyloxy, and the like.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)—, cycloalkyl-C(O)—, substitutedcycloalkyl-C(O)—, cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—,aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substitutedheteroaryl-C(O)—, heterocyclyl-C(O)—, and substitutedheterocyclyl-C(O)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein. For example, acylincludes the “acetyl” group CH₃C(O)—

“Acylamino” refers to the groups —NR²⁰C(O)alkyl, —NR²⁰C(O)substitutedalkyl, NR²⁰C(O)cycloalkyl, —NR²⁰C(O)substituted cycloalkyl,—NR²⁰C(O)cycloalkenyl, —NR²⁰C(O)substituted cycloalkenyl,—NR²⁰C(O)alkenyl, —NR²⁰C(O)substituted alkenyl, —NR²⁰C(O)alkynyl,—NR²⁰C(O)substituted alkynyl, —NR²⁰C(O)aryl, —NR²⁰C(O)substituted aryl,—NR²⁰C(O)heteroaryl, —NR²⁰C(O)substituted heteroaryl,—NR²⁰C(O)heterocyclic, and —NR²⁰C(O)substituted heterocyclic, whereinR²⁰ is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“Aminocarbonyl” or the term “aminoacyl” refers to the group—C(O)NR²¹R²², wherein R²¹ and R²² independently are selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic and where R²¹ and R²² are optionally joinedtogether with the nitrogen bound thereto to form a heterocyclic orsubstituted heterocyclic group, and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“Aminocarbonylamino” refers to the group —NR²¹C(O)NR²²R²³ where R²¹,R²², and R²³ are independently selected from hydrogen, alkyl, aryl orcycloalkyl, or where two R groups are joined to form a heterocyclylgroup.

The term “alkoxycarbonylamino” refers to the group —NRC(O)OR where eachR is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl,or heterocyclyl wherein alkyl, substituted alkyl, aryl, heteroaryl, andheterocyclyl are as defined herein.

The term “acyloxy” refers to the groups alkyl-C(O)O—, substitutedalkyl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—,aryl-C(O)O—, heteroaryl-C(O)O—, and heterocyclyl-C(O)O— wherein alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl,and heterocyclyl are as defined herein.

“Aminosulfonyl” refers to the group —SO₂NR²¹R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic and where R²¹ and R²²are optionally joined together with the nitrogen bound thereto to form aheterocyclic or substituted heterocyclic group and alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Sulfonylamino” refers to the group —NR²¹SO₂R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R²¹ andR²² are optionally joined together with the atoms bound thereto to forma heterocyclic or substituted heterocyclic group, and wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from6 to 18 carbon atoms having a single ring (such as is present in aphenyl group) or a ring system having multiple condensed rings (examplesof such aromatic ring systems include naphthyl, anthryl and indanyl)which condensed rings may or may not be aromatic, provided that thepoint of attachment is through an atom of an aromatic ring. This termincludes, by way of example, phenyl and naphthyl. Unless otherwiseconstrained by the definition for the aryl substituent, such aryl groupscan optionally be substituted with from 1 to 5 substituents, or from 1to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl,substituted alkoxy, substituted alkenyl, substituted alkynyl,substituted cycloalkyl, substituted cycloalkenyl, amino, substitutedamino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy,heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl and trihalomethyl.

“Aryloxy” refers to the group —O-aryl, wherein aryl is as definedherein, including, by way of example, phenoxy, naphthoxy, and the like,including optionally substituted aryl groups as also defined herein.

“Amino” refers to the group —NH₂.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl,substituted alkynyl, aryl, heteroaryl, and heterocyclyl provided that atleast one R is not hydrogen.

The term “azido” refers to the group —N₃.

“Carboxyl,” “carboxy” or “carboxylate” refers to —CO₂H or salts thereof.

“Carboxyl ester” or “carboxy ester” or the terms “carboxyalkyl” or“carboxylalkyl” refers to the groups —C(O)O-alkyl, —C(O)O-substitutedalkyl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl,—C(O)O-substituted alkynyl, —C(O)O-aryl, —C(O)O-substituted aryl,—C(O)O-cycloalkyl, —C(O)O-substituted cycloalkyl, —C(O)O-cycloalkenyl,—C(O)O-substituted cycloalkenyl, —C(O)O-heteroaryl, —C(O)O-substitutedheteroaryl, —C(O)O-heterocyclic, and —C(O)O-substituted heterocyclic,wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic areas defined herein.

“(Carboxyl ester)oxy” or “carbonate” refers to the groups—O—C(O)O-alkyl, —O—C(O)O-substituted alkyl, —O—C(O)O-alkenyl,—O—C(O)O-substituted alkenyl, —O—C(O)O— alkynyl, —O—C(O)O-substitutedalkynyl, —O—C(O)O-aryl, —O—C(O)O-substituted aryl, —O—C(O)O— cycloalkyl,—O—C(O)O-substituted cycloalkyl, —O—C(O)O-cycloalkenyl,—O—C(O)O-substituted cycloalkenyl, —O—C(O)O-heteroaryl,—O—C(O)O-substituted heteroaryl, —O—C(O)O-heterocyclic, and—O—C(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“Cyano” or “nitrile” refers to the group —CN.

“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atomshaving single or multiple cyclic rings including fused, bridged, andspiro ring systems. Examples of suitable cycloalkyl groups include, forinstance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyland the like. Such cycloalkyl groups include, by way of example, singlering structures such as cyclopropyl, cyclobutyl, cyclopentyl,cyclooctyl, and the like, or multiple ring structures such asadamantanyl, and the like.

The term “substituted cycloalkyl” refers to cycloalkyl groups havingfrom 1 to 5 substituents, or from 1 to 3 substituents, selected fromalkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

“Cycloalkenyl” refers to non-aromatic cyclic alkyl groups of from 3 to10 carbon atoms having single or multiple rings and having at least onedouble bond and preferably from 1 to 2 double bonds.

The term “substituted cycloalkenyl” refers to cycloalkenyl groups havingfrom 1 to 5 substituents, or from 1 to 3 substituents, selected fromalkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino,substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano,halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy,thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substitutedthioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

“Cycloalkynyl” refers to non-aromatic cycloalkyl groups of from 5 to 10carbon atoms having single or multiple rings and having at least onetriple bond.

“Cycloalkoxy” refers to —O-cycloalkyl.

“Cycloalkenyloxy” refers to —O-cycloalkenyl.

“Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Heteroaryl” refers to an aromatic group of from 1 to 15 carbon atoms,such as from 1 to 10 carbon atoms and 1 to 10 heteroatoms selected fromthe group consisting of oxygen, nitrogen, and sulfur within the ring.Such heteroaryl groups can have a single ring (such as, pyridinyl,imidazolyl or furyl) or multiple condensed rings in a ring system (forexample as in groups such as, indolizinyl, quinolinyl, benzofuran,benzimidazolyl or benzothienyl), wherein at least one ring within thering system is aromatic and at least one ring within the ring system isaromatic, provided that the point of attachment is through an atom of anaromatic ring. In certain embodiments, the nitrogen and/or sulfur ringatom(s) of the heteroaryl group are optionally oxidized to provide forthe N-oxide (N→O), sulfinyl, or sulfonyl moieties. This term includes,by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, andfuranyl. Unless otherwise constrained by the definition for theheteroaryl substituent, such heteroaryl groups can be optionallysubstituted with 1 to 5 substituents, or from 1 to 3 substituents,selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkoxy, substituted alkenyl, substituted alkynyl, substitutedcycloalkyl, substituted cycloalkenyl, amino, substituted amino,aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy,heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl, andtrihalomethyl.

The term “heteroaralkyl” refers to the groups -alkylene-heteroaryl wherealkylene and heteroaryl are defined herein. This term includes, by wayof example, pyridylmethyl, pyridylethyl, indolylmethyl, and the like.

“Heteroaryloxy” refers to —O-heteroaryl.

“Heterocycle,” “heterocyclic,” “heterocycloalkyl,” and “heterocyclyl”refer to a saturated or unsaturated group having a single ring ormultiple condensed rings, including fused bridged and spiro ringsystems, and having from 3 to 20 ring atoms, including 1 to 10 heteroatoms. These ring atoms are selected from the group consisting ofnitrogen, sulfur, or oxygen, wherein, in fused ring systems, one or moreof the rings can be cycloalkyl, aryl, or heteroaryl, provided that thepoint of attachment is through the non-aromatic ring. In certainembodiments, the nitrogen and/or sulfur atom(s) of the heterocyclicgroup are optionally oxidized to provide for the N-oxide, —S(O)—, or—SO₂— moieties.

Examples of heterocycles and heteroaryls include, but are not limitedto, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine,tetrahydrofuranyl, and the like.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5, or from 1 to 3 substituents, selected from alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl,—SO₂-heteroaryl, and fused heterocycle.

“Heterocyclyloxy” refers to the group —O-heterocyclyl.

The term “heterocyclylthio” refers to the group heterocyclic-S—.

The term “heterocyclene” refers to the diradical group formed from aheterocycle, as defined herein.

The term “hydroxyamino” refers to the group —NHOH.

“Nitro” refers to the group —NO₂.

“Oxo” refers to the atom (═O).

“Sulfonyl” refers to the group SO₂-alkyl, SO₂-substituted alkyl,SO₂-alkenyl, SO₂-substituted alkenyl, SO₂-cycloalkyl, SO₂-substitutedcycloalkyl, SO₂-cycloalkenyl, SO₂-substituted cylcoalkenyl, SO₂-aryl,SO₂-substituted aryl, SO₂-heteroaryl, SO₂-substituted heteroaryl,SO₂-heterocyclic, and SO₂-substituted heterocyclic, wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein. Sulfonyl includes, by way of example, methyl-SO₂—, phenyl-SO₂—,and 4-methylphenyl-SO₂—.

“Sulfonyloxy” refers to the group —OSO₂-alkyl, OSO₂-substituted alkyl,OSO₂-alkenyl, OSO₂-substituted alkenyl, OSO₂-cycloalkyl,OSO₂-substituted cycloalkyl, OSO₂-cycloalkenyl, OSO₂-substitutedcylcoalkenyl, OSO₂-aryl, OSO₂-substituted aryl, OSO₂-heteroaryl,OSO₂-substituted heteroaryl, OSO₂-heterocyclic, and OSO₂ substitutedheterocyclic, wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic are as defined herein.

The term “aminocarbonyloxy” refers to the group —OC(O)NRR where each Ris independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl,or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl andheterocyclic are as defined herein.

“Thiol” refers to the group —SH.

“Thioxo” or the term “thioketo” refers to the atom (═S).

“Alkylthio” or the term “thioalkoxy” refers to the group —S-alkyl,wherein alkyl is as defined herein. In certain embodiments, sulfur maybe oxidized to —S(O)—. The sulfoxide may exist as one or morestereoisomers.

The term “substituted thioalkoxy” refers to the group —S-substitutedalkyl.

The term “thioaryloxy” refers to the group aryl-S— wherein the arylgroup is as defined herein including optionally substituted aryl groupsalso defined herein.

The term “thioheteroaryloxy” refers to the group heteroaryl-S— whereinthe heteroaryl group is as defined herein including optionallysubstituted aryl groups as also defined herein.

The term “thioheterocyclooxy” refers to the group heterocyclyl-S—wherein the heterocyclyl group is as defined herein including optionallysubstituted heterocyclyl groups as also defined herein.

In addition to the disclosure herein, the term “substituted,” when usedto modify a specified group or radical, can also mean that one or morehydrogen atoms of the specified group or radical are each, independentlyof one another, replaced with the same or different substituent groupsas defined below.

In addition to the groups disclosed with respect to the individual termsherein, substituent groups for substituting for one or more hydrogens(any two hydrogens on a single carbon can be replaced with ═O, ═NR⁷⁰,═N—OR⁷⁰, ═N₂ or ═S) on saturated carbon atoms in the specified group orradical are, unless otherwise specified, —R⁶⁰, halo, ═O, —OR⁷⁰, —SR⁷⁰,—NR⁸⁰R⁸⁰, trihalomethyl, —CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —SO₂R⁷⁰,—SO₂O⁻M⁺, —SO₂OR⁷⁰, —OSO₂R⁷⁰, —OSO₂O⁻M⁺, —OSO₂OR⁷⁰, —P(O)(O⁻)₂(M⁺)₂,—P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰,—C(O)O⁻M⁺, —C(O)OR⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)NR⁸⁰R⁸⁰,—OC(O)R⁷⁰, —OC(S)R⁷⁰, —OC(O)O⁻M⁺, —OC(O)OR⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰,—NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰ isselected from the group consisting of optionally substituted alkyl,cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl and heteroarylalkyl, each R⁷⁰ is independentlyhydrogen or R⁶⁰; each R⁸⁰ is independently R⁷⁰ or alternatively, twoR^(80')s, taken together with the nitrogen atom to which they arebonded, form a 5-, 6- or 7-membered heterocycloalkyl which mayoptionally include from 1 to 4 of the same or different additionalheteroatoms selected from the group consisting of O, N and S, of which Nmay have —H or C₁-C₃ alkyl substitution; and each M⁺ is a counter ionwith a net single positive charge. Each M⁺ may independently be, forexample, an alkali ion, such as K⁺, Na⁺, Li⁺; an ammonium ion, such as⁺N(R⁶⁰)₄; or an alkaline earth ion, such as [Ca²⁺]_(0.5), [Mg²⁺]_(0.5),or [Ba²⁺]_(0.5) (“subscript 0.5 means that one of the counter ions forsuch divalent alkali earth ions can be an ionized form of a compound ofthe invention and the other a typical counter ion such as chloride, ortwo ionized compounds disclosed herein can serve as counter ions forsuch divalent alkali earth ions, or a doubly ionized compound of theinvention can serve as the counter ion for such divalent alkali earthions). As specific examples, —NR⁸⁰R⁸⁰ is meant to include —NH₂,—NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl andN-morpholinyl.

In addition to the disclosure herein, substituent groups for hydrogenson unsaturated carbon atoms in “substituted” alkene, alkyne, aryl andheteroaryl groups are, unless otherwise specified, —R⁶⁰, halo, —O⁻M⁺,—OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —NR⁸⁰R⁸⁰, trihalomethyl, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, —N₃, —SO₂R⁷⁰, —SO₃ ⁻M⁺, —SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃ ⁻M⁺,—OSO₃R⁷⁰, —PO₃ ⁻²(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰,—C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂ ⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰,—C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂ ⁻M⁺, —OCO₂R⁷⁰, —OC(S)OR⁷⁰,—NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰,R⁷⁰, R⁸⁰ and M⁺ are as previously defined, provided that in case ofsubstituted alkene or alkyne, the substituents are not —O⁻M⁺, —OR⁷⁰,—SR⁷⁰, or —S⁻M⁺.

In addition to the groups disclosed with respect to the individual termsherein, substituent groups for hydrogens on nitrogen atoms in“substituted” heteroalkyl and cycloheteroalkyl groups are, unlessotherwise specified, —R⁶⁰, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —NR⁸⁰R⁸⁰,trihalomethyl, —CF₃, —CN, —NO, —NO₂, —S(O)₂R⁷⁰, —S(O)₂O⁻M⁺, —S(O)₂OR⁷⁰,—OS(O)₂R⁷⁰, —OS(O)₂O⁻M⁺, —OS(O)₂OR⁷⁰, —P(O)(O⁻)₂(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺,—P(O)(OR⁷⁰)(OR⁷⁰), —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —C(O)OR⁷⁰,—C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰,—OC(O)OR⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰C(O)OR⁷⁰,—NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and—NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ are as previouslydefined.

In addition to the disclosure herein, in a certain embodiment, a groupthat is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3substituents, 1 or 2 substituents, or 1 substituent.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,which is further substituted by a substituted aryl group, etc.) are notintended for inclusion herein. In such cases, the maximum number of suchsubstitutions is three. For example, serial substitutions of substitutedaryl groups specifically contemplated herein are limited to substitutedaryl-(substituted aryl)-substituted aryl.

Unless indicated otherwise, the nomenclature of substituents that arenot explicitly defined herein are arrived at by naming the terminalportion of the functionality followed by the adjacent functionalitytoward the point of attachment. For example, the substituent“arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-O—C(O)—.

As to any of the groups disclosed herein which contain one or moresubstituents, it is understood, of course, that such groups do notcontain any substitution or substitution patterns which are stericallyimpractical and/or synthetically non-feasible. In addition, the subjectcompounds include all stereochemical isomers arising from thesubstitution of these compounds.

The term “pharmaceutically acceptable salt” means a salt which isacceptable for administration to a patient, such as a mammal (salts withcounterions having acceptable mammalian safety for a given dosageregime). Such salts can be derived from pharmaceutically acceptableinorganic or organic bases and from pharmaceutically acceptableinorganic or organic acids. “Pharmaceutically acceptable salt” refers topharmaceutically acceptable salts of a compound, which salts are derivedfrom a variety of organic and inorganic counter ions well known in theart and include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, and the like; and when themolecule contains a basic functionality, salts of organic or inorganicacids, such as hydrochloride, hydrobromide, formate, tartrate, besylate,mesylate, acetate, maleate, oxalate, and the like.

The term “salt thereof” means a compound formed when a proton of an acidis replaced by a cation, such as a metal cation or an organic cation andthe like. Where applicable, the salt is a pharmaceutically acceptablesalt, although this is not required for salts of intermediate compoundsthat are not intended for administration to a patient. By way ofexample, salts of the present compounds include those wherein thecompound is protonated by an inorganic or organic acid to form a cation,with the conjugate base of the inorganic or organic acid as the anioniccomponent of the salt.

“Solvate” refers to a complex formed by combination of solvent moleculeswith molecules or ions of the solute. The solvent can be an organiccompound, an inorganic compound, or a mixture of both. Some examples ofsolvents include, but are not limited to, methanol,N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water.When the solvent is water, the solvate formed is a hydrate.

“Stereoisomer” and “stereoisomers” refer to compounds that have sameatomic connectivity but different atomic arrangement in space.Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers,and diastereomers.

“Tautomer” refers to alternate forms of a molecule that differ only inelectronic bonding of atoms and/or in the position of a proton, such asenol-keto and imine-enamine tautomers, or the tautomeric forms ofheteroaryl groups containing a —N═C(H)—NH— ring atom arrangement, suchas pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. Aperson of ordinary skill in the art would recognize that othertautomeric ring atom arrangements are possible.

It will be appreciated that the term “or a salt or solvate orstereoisomer thereof” is intended to include all permutations of salts,solvates and stereoisomers, such as a solvate of a pharmaceuticallyacceptable salt of a stereoisomer of subject compound.

“Pharmaceutically effective amount” and “therapeutically effectiveamount” refer to an amount of a compound sufficient to treat a specifieddisorder or disease or one or more of its symptoms and/or to prevent theoccurrence of the disease or disorder. In reference to tumorigenicproliferative disorders, a pharmaceutically or therapeutically effectiveamount comprises an amount sufficient to, among other things, cause thetumor to shrink or decrease the growth rate of the tumor.

“Patient” refers to human and non-human subjects, especially mammaliansubjects.

The term “treating” or “treatment” as used herein means the treating ortreatment of a disease or medical condition in a patient, such as amammal (particularly a human) that includes: (a) preventing the diseaseor medical condition from occurring, such as, prophylactic treatment ofa subject; (b) ameliorating the disease or medical condition, such as,eliminating or causing regression of the disease or medical condition ina patient; (c) suppressing the disease or medical condition, for exampleby, slowing or arresting the development of the disease or medicalcondition in a patient; or (d) alleviating a symptom of the disease ormedical condition in a patient.

Representative Embodiments

The following substituents and values are intended to providerepresentative examples of various aspects and embodiments. Theserepresentative values are intended to further define and illustrate suchaspects and embodiments and are not intended to exclude otherembodiments or to limit the scope of the present disclosure. In thisregard, the representation that a particular value or substituent ispreferred is not intended in any way to exclude other values orsubstituents from the present disclosure unless specifically indicated.

These compounds may contain one or more chiral centers and therefore,the embodiments are directed to racemic mixtures; pure stereoisomers(i.e., enantiomers or diastereomers); stereoisomer-enriched mixtures andthe like unless otherwise indicated. When a particular stereoisomer isshown or named herein, it will be understood by those skilled in the artthat minor amounts of other stereoisomers may be present in thecompositions unless otherwise indicated, provided that the desiredutility of the composition as a whole is not eliminated by the presenceof such other isomers.

The compositions of the present disclosure include compounds of formulaeI-IV, shown below. Pharmaceutical compositions and methods of thepresent disclosure also contemplate compounds of formulae I-IV.

Formula I

Embodiments of the present disclosure include a compound of formula (I):

wherein

R¹¹ is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy, amino,substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl,aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,sulfide, substituted sulfide, and SF₅;

Y¹ and Y² are independently selected from hydrogen and alkyl; and

Ar¹ is selected from aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;

or a salt or stereoisomer thereof.

In formula (I), Ar¹ is selected from aryl, substituted aryl, heteroaryl,and substituted heteroaryl. In certain embodiments, Ar¹ is aryl orsubstituted aryl. In certain embodiments, Ar¹ is aryl. In certainembodiments, Ar¹ is substituted aryl. In certain embodiments, Ar¹ isheteroaryl or substituted heteroaryl. In certain embodiments, Ar¹ isheteroaryl. In certain embodiments, Ar¹ is substituted heteroaryl.

Formula II

Embodiments of the present disclosure include a compound of formula(II):

wherein

R¹¹ is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy, amino,substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl,aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,sulfide, substituted sulfide, and SF₅;

Y¹ and Y² are independently selected from hydrogen and alkyl;

Q is C or N; and

R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ are independently selected from hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, halogen, cyano, hydroxyl, alkoxy, substitutedalkoxy, amino, substituted amino, acylamino, aminocarbonylamino,alkoxycarbonylamino, acyl, carboxyl, carboxyl ester, aminoacyl,aminocarbonyloxy, nitro, sulfonyl, sulfonylamino, aminosulfonyl, sulfurpentafluoride, aryl, substituted aryl, cycloalkyl, substitutedcycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, andsubstituted heterocyclyl, or R¹⁴ and R¹⁵ together with the carbon atomsto which they are attached form aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;

or a salt or stereoisomer thereof.

Aspects of the present embodiments also include a compound of formula(IIa):

wherein

R¹¹ is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy, amino,substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl,aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,sulfide, substituted sulfide, and SF₅;

Y¹ and Y² are independently selected from hydrogen and alkyl;

Q is C or N; and

R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ are independently selected from hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, halogen, cyano, hydroxyl, alkoxy, substitutedalkoxy, amino, substituted amino, acylamino, aminocarbonylamino,alkoxycarbonylamino, acyl, carboxyl, carboxyl ester, aminoacyl,aminocarbonyloxy, nitro, sulfonyl, sulfonylamino, aminosulfonyl, sulfurpentafluoride, aryl, substituted aryl, cycloalkyl, substitutedcycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, andsubstituted heterocyclyl, or R¹⁴ and R¹⁵ together with the carbon atomsto which they are attached form aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;

or a salt or stereoisomer thereof.

Reference to formula (II) is meant to include compounds of formula (II)and (IIa).

In formula (II), Q is C or N. In certain embodiments, Q is C. In certainembodiments, Q is N. In certain embodiments where Q is N, R¹³ is absent.

In formula (II), R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ are independently selectedfrom hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, halogen, cyano, hydroxyl, alkoxy,substituted alkoxy, amino, substituted amino, acylamino,aminocarbonylamino, alkoxycarbonylamino, acyl, carboxyl, carboxyl ester,aminoacyl, aminocarbonyloxy, nitro, sulfonyl, sulfonylamino,aminosulfonyl, sulfur pentafluoride, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclyl, and substituted heterocyclyl, or R¹⁴ and R¹⁵ together withthe carbon atoms to which they are attached form aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclyl, or substitutedheterocyclyl.

In certain embodiments, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ are independentlyselected from hydrogen, alkyl, substituted alkyl, halogen, cyano,hydroxyl, alkoxy, substituted alkoxy, amino, substituted amino,acylamino, aminocarbonylamino, acyl, aminoacyl, aminocarbonyloxy, sulfurpentafluoride, aryl, substituted aryl, cycloalkyl, substitutedcycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, andsubstituted heterocyclyl, or R¹⁴ and R¹⁵ together with the carbon atomsto which they are attached form aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclyl, or substituted heterocyclyl.

In certain embodiments, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ are independentlyselected from hydrogen, alkyl, substituted alkyl, halogen, cyano,alkoxy, substituted alkoxy, sulfur pentafluoride, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclyl, and substituted heterocyclyl, or R¹⁴ and R¹⁵together with the carbon atoms to which they are attached form aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, orsubstituted heterocyclyl.

In certain embodiments, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ are independentlyselected from hydrogen, alkyl, substituted alkyl, halogen, cyano,alkoxy, substituted alkoxy, sulfur pentafluoride, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, heteroaryl, and substitutedheteroaryl, or R¹⁴ and R¹⁵ together with the carbon atoms to which theyare attached form a heterocyclyl or substituted heterocyclyl 5 to8-membered ring.

In certain embodiments, R¹⁴ and R¹⁵ together with the carbon atoms towhich they are attached form a heterocyclyl or substituted heterocyclyl5 to 8-membered ring. In certain embodiments, R¹², R¹³, R¹⁴, R¹⁵, andR¹⁶ are independently selected from hydrogen, alkyl, substituted alkyl,halogen, cyano, alkoxy, substituted alkoxy, sulfur pentafluoride,cycloalkyl, substituted, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclyl, and substituted heterocyclyl.

In certain embodiments, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ are independentlyselected from hydrogen, alkyl, substituted alkyl, and halogen. Incertain embodiments, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ are independentlyselected from hydrogen, halogen, alkoxy, and substituted alkoxy. Incertain embodiments, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ are independentlyselected from hydrogen, alkyl, substituted alkyl, halogen, alkoxy,substituted alkoxy, cycloalkyl, substituted cycloalkyl, heterocyclyl,and substituted heterocyclyl. In certain embodiments, R¹², R¹³, R¹⁴,R¹⁵, and R¹⁶ are independently selected from hydrogen, alkyl,substituted alkyl, cyano, alkoxy, substituted alkoxy, sulfurpentafluoride, heteroaryl, substituted heteroaryl, heterocyclyl, andsubstituted heterocyclyl.

In certain embodiments, R¹² is selected from hydrogen, alkyl,substituted alkyl, and halogen. In certain embodiments, R¹³ is selectedfrom hydrogen, halogen, alkoxy, and substituted alkoxy. In certainembodiments, R¹⁴ is selected from hydrogen, alkyl, substituted alkyl,halogen, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl,heterocyclyl, and substituted heterocyclyl. In certain embodiments, R¹⁵is selected from hydrogen, alkyl, substituted alkyl, cyano, alkoxy,substituted alkoxy, sulfur pentafluoride, heteroaryl, substitutedheteroaryl, heterocyclyl, and substituted heterocyclyl. In certainembodiments, R¹⁶ is selected from hydrogen, alkyl, substituted alkyl,and halogen.

In formula (IIa), in certain embodiments, the compound is opticallyactive. In certain embodiments, there is an enantiomeric excess of 90%or more. In certain embodiments, there is an enantiomeric excess of 95%or more. In certain embodiments, there is an enantiomeric excess of 99%or more.

Formula III

Embodiments of the present disclosure include a compound of formula(III):

wherein

R¹¹ is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy, amino,substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl,aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,sulfide, substituted sulfide, and SF₅;

Y¹ and Y² are independently selected from hydrogen and alkyl; and

R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ are independently selected from hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, halogen, cyano, hydroxyl, alkoxy, substitutedalkoxy, amino, substituted amino, acylamino, aminocarbonylamino,alkoxycarbonylamino, acyl, carboxyl, carboxyl ester, aminoacyl,aminocarbonyloxy, nitro, sulfonyl, sulfonylamino, aminosulfonyl, sulfurpentafluoride, aryl, substituted aryl, cycloalkyl, substitutedcycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, andsubstituted heterocyclyl, or R¹⁴ and R¹⁵ together with the carbon atomsto which they are attached form aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;

or a salt or stereoisomer thereof.

Aspects of the present embodiments also include a compound of formula(IIIa):

wherein

R¹¹ is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy, amino,substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl,aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,sulfide, substituted sulfide, and SF₅;

Y¹ and Y² are independently selected from hydrogen and alkyl; and

R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ are independently selected from hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, halogen, cyano, hydroxyl, alkoxy, substitutedalkoxy, amino, substituted amino, acylamino, aminocarbonylamino,alkoxycarbonylamino, acyl, carboxyl, carboxyl ester, aminoacyl,aminocarbonyloxy, nitro, sulfonyl, sulfonylamino, aminosulfonyl, sulfurpentafluoride, aryl, substituted aryl, cycloalkyl, substitutedcycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, andsubstituted heterocyclyl, or R¹⁴ and R¹⁵ together with the carbon atomsto which they are attached form aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;

or a salt or stereoisomer thereof.

Reference to formula (III) is meant to include compounds of formula(III) and (IIIa).

In formula (III), R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ are independently selectedfrom hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, halogen, cyano, hydroxyl, alkoxy,substituted alkoxy, amino, substituted amino, acylamino,aminocarbonylamino, alkoxycarbonylamino, acyl, carboxyl, carboxyl ester,aminoacyl, aminocarbonyloxy, nitro, sulfonyl, sulfonylamino,aminosulfonyl, sulfur pentafluoride, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclyl, and substituted heterocyclyl, or R¹⁴ and R¹⁵ together withthe carbon atoms to which they are attached form aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclyl, or substitutedheterocyclyl.

In certain embodiments, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ are independentlyselected from hydrogen, alkyl, substituted alkyl, halogen, cyano,hydroxyl, alkoxy, substituted alkoxy, amino, substituted amino,acylamino, aminocarbonylamino, acyl, aminoacyl, aminocarbonyloxy, sulfurpentafluoride, aryl, substituted aryl, cycloalkyl, substitutedcycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, andsubstituted heterocyclyl, or R¹⁴ and R¹⁵ together with the carbon atomsto which they are attached form aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclyl, or substituted heterocyclyl.

In certain embodiments, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ are independentlyselected from hydrogen, alkyl, substituted alkyl, halogen, cyano,alkoxy, substituted alkoxy, sulfur pentafluoride, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclyl, and substituted heterocyclyl, or R¹⁴ and R¹⁵together with the carbon atoms to which they are attached form aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, orsubstituted heterocyclyl.

In certain embodiments, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ are independentlyselected from hydrogen, alkyl, substituted alkyl, halogen, cyano,alkoxy, substituted alkoxy, sulfur pentafluoride, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, heteroaryl, and substitutedheteroaryl, or R¹⁴ and R¹⁵ together with the carbon atoms to which theyare attached form a heterocyclyl or substituted heterocyclyl 5 to8-membered ring.

In certain embodiments, R¹⁴ and R¹⁵ together with the carbon atoms towhich they are attached form a heterocyclyl or substituted heterocyclyl5 to 8-membered ring. In certain embodiments, R¹², R¹³, R¹⁴, R¹⁵, andR¹⁶ are independently selected from hydrogen, alkyl, substituted alkyl,halogen, cyano, alkoxy, substituted alkoxy, sulfur pentafluoride,cycloalkyl, substituted, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclyl, and substituted heterocyclyl.

In certain embodiments, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ are independentlyselected from hydrogen, alkyl, substituted alkyl, and halogen. Incertain embodiments, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ are independentlyselected from hydrogen, halogen, alkoxy, and substituted alkoxy. Incertain embodiments, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ are independentlyselected from hydrogen, alkyl, substituted alkyl, halogen, alkoxy,substituted alkoxy, cycloalkyl, substituted cycloalkyl, heterocyclyl,and substituted heterocyclyl. In certain embodiments, R¹², R¹³, R¹⁴,R¹⁵, and R¹⁶ are independently selected from hydrogen, alkyl,substituted alkyl, cyano, alkoxy, substituted alkoxy, sulfurpentafluoride, heteroaryl, substituted heteroaryl, heterocyclyl, andsubstituted heterocyclyl.

In certain embodiments, R¹² is selected from hydrogen, alkyl,substituted alkyl, and halogen. In certain embodiments, R¹³ is selectedfrom hydrogen, halogen, alkoxy, and substituted alkoxy. In certainembodiments, R¹⁴ is selected from hydrogen, alkyl, substituted alkyl,halogen, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl,heterocyclyl, and substituted heterocyclyl. In certain embodiments, R¹⁵is selected from hydrogen, alkyl, substituted alkyl, cyano, alkoxy,substituted alkoxy, sulfur pentafluoride, heteroaryl, substitutedheteroaryl, heterocyclyl, and substituted heterocyclyl. In certainembodiments, R¹⁶ is selected from hydrogen, alkyl, substituted alkyl,and halogen.

In formula (IIIa), in certain embodiments, the compound is opticallyactive. In certain embodiments, there is an enantiomeric excess of 90%or more. In certain embodiments, there is an enantiomeric excess of 95%or more. In certain embodiments, there is an enantiomeric excess of 99%or more.

Formula IV

Embodiments of the present disclosure include a compound of formula(IV):

wherein

R¹¹ is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy, amino,substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl,aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,sulfide, substituted sulfide, and SF₅;

Y¹ and Y² are independently selected from hydrogen and alkyl; and

R¹², R¹⁴, R¹⁵, and R¹⁶ are independently selected from hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, halogen, cyano, hydroxyl, alkoxy, substituted alkoxy, amino,substituted amino, acylamino, aminocarbonylamino, alkoxycarbonylamino,acyl, carboxyl, carboxyl ester, aminoacyl, aminocarbonyloxy, nitro,sulfonyl, sulfonylamino, aminosulfonyl, sulfur pentafluoride, aryl,substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, orR¹⁴ and R¹⁵ together with the carbon atoms to which they are attachedform aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclyl, or substituted heterocyclyl;

or a salt or stereoisomer thereof.

Aspects of the present embodiments also include a compound of formula(IVa):

wherein

R¹¹ is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy, amino,substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl,aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,sulfide, substituted sulfide, and SF₅;

Y¹ and Y² are independently selected from hydrogen and alkyl; and

R¹², R¹⁴, R¹⁵, and R¹⁶ are independently selected from hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, halogen, cyano, hydroxyl, alkoxy, substituted alkoxy, amino,substituted amino, acylamino, aminocarbonylamino, alkoxycarbonylamino,acyl, carboxyl, carboxyl ester, aminoacyl, aminocarbonyloxy, nitro,sulfonyl, sulfonylamino, aminosulfonyl, sulfur pentafluoride, aryl,substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, orR¹⁴ and R¹⁵ together with the carbon atoms to which they are attachedform aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclyl, or substituted heterocyclyl;

or a salt or stereoisomer thereof.

Reference to formula (IV) is meant to include compounds of formula (IV)and (IVa).

In formula (IV), R¹², R¹⁴, R¹⁵, and R¹⁶ are independently selected fromhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, halogen, cyano, hydroxyl, alkoxy,substituted alkoxy, amino, substituted amino, acylamino,aminocarbonylamino, alkoxycarbonylamino, acyl, carboxyl, carboxyl ester,aminoacyl, aminocarbonyloxy, nitro, sulfonyl, sulfonylamino,aminosulfonyl, sulfur pentafluoride, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclyl, and substituted heterocyclyl, or R¹⁴ and R¹⁵ together withthe carbon atoms to which they are attached form aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclyl, or substitutedheterocyclyl. In certain embodiments of formula (IV), R¹³ is absent.

In certain embodiments, R¹², R¹⁴, R¹⁵, and R¹⁶ are independentlyselected from hydrogen, alkyl, substituted alkyl, halogen, cyano,hydroxyl, alkoxy, substituted alkoxy, amino, substituted amino,acylamino, aminocarbonylamino, acyl, aminoacyl, aminocarbonyloxy, sulfurpentafluoride, aryl, substituted aryl, cycloalkyl, substitutedcycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, andsubstituted heterocyclyl, or R¹⁴ and R¹⁵ together with the carbon atomsto which they are attached form aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclyl, or substituted heterocyclyl.

In certain embodiments, R¹², R¹⁴, R¹⁵, and R¹⁶ are independentlyselected from hydrogen, alkyl, substituted alkyl, halogen, cyano,alkoxy, substituted alkoxy, sulfur pentafluoride, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclyl, and substituted heterocyclyl, or R¹⁴ and R¹⁵together with the carbon atoms to which they are attached form aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, orsubstituted heterocyclyl.

In certain embodiments, R¹², R¹⁴, R¹⁵, and R¹⁶ are independentlyselected from hydrogen, alkyl, substituted alkyl, halogen, cyano,alkoxy, substituted alkoxy, sulfur pentafluoride, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, heteroaryl, and substitutedheteroaryl, or R¹⁴ and R¹⁵ together with the carbon atoms to which theyare attached form a heterocyclyl or substituted heterocyclyl 5 to8-membered ring.

In certain embodiments, R¹⁴ and R¹⁵ together with the carbon atoms towhich they are attached form a heterocyclyl or substituted heterocyclyl5 to 8-membered ring. In certain embodiments, R¹², R¹⁴, R¹⁵, and R¹⁶ areindependently selected from hydrogen, alkyl, substituted alkyl, halogen,cyano, alkoxy, substituted alkoxy, sulfur pentafluoride, cycloalkyl,substituted, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclyl, and substituted heterocyclyl.

In certain embodiments, R¹², R¹⁴, R¹⁵, and R¹⁶ are independentlyselected from hydrogen, alkyl, substituted alkyl, and halogen. Incertain embodiments, R¹², R¹⁴, R¹⁵, and R¹⁶ are independently selectedfrom hydrogen, halogen, alkoxy, and substituted alkoxy. In certainembodiments, R¹², R¹⁴, R¹⁵, and R¹⁶ are independently selected fromhydrogen, alkyl, substituted alkyl, halogen, alkoxy, substituted alkoxy,cycloalkyl, substituted cycloalkyl, heterocyclyl, and substitutedheterocyclyl. In certain embodiments, R¹², R¹⁴, R¹⁵, and R¹⁶ areindependently selected from hydrogen, alkyl, substituted alkyl, cyano,alkoxy, substituted alkoxy, sulfur pentafluoride, heteroaryl,substituted heteroaryl, heterocyclyl, and substituted heterocyclyl.

In certain embodiments, R¹² is selected from hydrogen, alkyl,substituted alkyl, and halogen. In certain embodiments, R¹³ is absent.In certain embodiments, R¹⁴ is selected from hydrogen, alkyl,substituted alkyl, halogen, alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. Incertain embodiments, R¹⁵ is selected from hydrogen, alkyl, substitutedalkyl, cyano, alkoxy, substituted alkoxy, sulfur pentafluoride,heteroaryl, substituted heteroaryl, heterocyclyl, and substitutedheterocyclyl. In certain embodiments, R¹⁶ is selected from hydrogen,alkyl, substituted alkyl, and halogen.

In formula (IVa), in certain embodiments, the compound is opticallyactive. In certain embodiments, there is an enantiomeric excess of 90%or more. In certain embodiments, there is an enantiomeric excess of 95%or more. In certain embodiments, there is an enantiomeric excess of 99%or more.

Certain Embodiments of Formulae I-IV

With reference to formulae I-IV, the portion of the compound as shown inthe following formula:

includes at least two chiral centers, and thus at least fourstereoisomers. For clarity the numbering of the ring system is shownbelow with optional substituents omitted.

With continued reference to formulae I-IV, the (1,9a) cis diastereomerhas the structure:

and the (1,9a) trans diastereomer has the structure:

In certain embodiments of formulae I-IV, the (1,9a) trans diastereomerhas the structure:

In formulae I-IV, R¹¹ is selected from hydrogen, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, hydroxy, alkoxy, substitutedalkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano,halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, sulfide, substituted sulfide, and SF₅.

In certain embodiments, R¹¹ is selected from hydrogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy,substituted alkoxy, amino, substituted amino, cyano, halogen, acyl andaminoacyl.

In certain embodiments, R¹¹ is hydrogen. In certain embodiments, R¹¹ isalkyl or substituted alkyl. In certain embodiments, R¹¹ is alkyl, suchas a C₁₋₆ alkyl, or C₁₋₃ alkyl. In certain embodiments, R¹¹ issubstituted alkyl, such as a substituted C₁₋₆ alkyl, or substituted C₁₋₃alkyl. In certain embodiments, R¹¹ is methyl. In certain embodiments,R¹¹ is trifluoromethyl. In certain embodiments, R¹¹ is cycloalkyl orsubstituted cycloalkyl. In certain embodiments, R¹¹ is cycloalkyl, suchas a C₃₋₈ cycloalkyl, or C₃₋₆ cycloalkyl. In certain embodiments, R¹¹ issubstituted cycloalkyl, such as a substituted C₃₋₈ cycloalkyl, orsubstituted C₃₋₆ cycloalkyl. In certain embodiments, R¹¹ is alkoxy orsubstituted alkoxy. In certain embodiments, R¹¹ is alkoxy, such as aC₁₋₆ alkoxy, or C₁₋₃ alkoxy. In certain embodiments, R¹¹ is substitutedalkoxy, such as a substituted C₁₋₆ alkoxy, or substituted C₁₋₃ alkoxy.In certain embodiments, R¹¹ is methoxy. In certain embodiments, R¹¹ isamino or substituted amino. In certain embodiments, R¹¹ isdimethylamino. In certain embodiments, R¹¹ is cyano. In certainembodiments, R¹¹ is halogen. In certain embodiments, R¹¹ is fluoro. Incertain embodiments, R¹¹ is chloro. In certain embodiments, R¹¹ is acyl.In certain embodiments, R¹¹ is aminoacyl.

In certain embodiments, R¹¹ is carboxyl, carboxyl ester, nitro, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, sulfide, substituted sulfide,and SF₅. In certain embodiments, R¹¹ is carboxyl or carboxyl ester. Incertain embodiments, R¹¹ is nitro. In certain embodiments, R¹¹ isalkenyl or substituted alkenyl. In certain embodiments, R¹¹ is alkenyl,such as a C₂₋₆ alkenyl, or C₂₋₄ alkenyl. In certain embodiments, R¹¹ issubstituted alkenyl, such as a substituted C₂₋₆ alkenyl, or substitutedC₂₋₄ alkenyl. In certain embodiments, R¹¹ is alkynyl or substitutedalkynyl. In certain embodiments, R¹¹ is alkynyl, such as a C₂₋₆ alkynyl,or C₂₋₄ alkynyl. In certain embodiments, R¹¹ is substituted alkynyl,such as a substituted C₂₋₆ alkynyl, or substituted C₂₋₄ alkynyl. Incertain embodiments, R¹¹ is aryl or substituted aryl. In certainembodiments, R¹¹ is aryl. In certain embodiments, R¹¹ is substitutedaryl. In certain embodiments, R¹¹ is heteroaryl or substitutedheteroaryl. In certain embodiments, R¹¹ is heteroaryl. In certainembodiments, R¹¹ is substituted heteroaryl. In certain embodiments, R¹¹is sulfide, substituted sulfide or SF₅. In certain embodiments, R¹¹ issulfide. In certain embodiments, R¹¹ is substituted sulfide. In certainembodiments, R¹¹ is SF₅.

In formulae I-IV, Y¹ and Y² are independently selected from hydrogen andalkyl. In certain embodiments, Y¹ and Y² are hydrogen. In certainembodiments, Y¹ and Y² are alkyl. In certain embodiments, one of Y¹ andY² is hydrogen and the other of Y¹ and Y² is alkyl.

Embodiments of the compounds of formulae I-IV are shown in the followingtable.

TABLE 1

Com- pound R¹¹ Y¹ Y² Ar¹ 1 F H H

2 F H H

3 F H H

4 F H H

5 Cl H H

6 F H H

7 F H H

8 F H H

9 F H H

10 F H H

11 F H H

12 F H H

13 F H H

14 F H H

15 F H H

16 F H H

17 F H H

18 F H H

19 F H H

20 F H H

21 F H H

22 F H H

23 F H H

24 F H H

25 F H H

26 F H H

27 F H H

28 F H H

29 F H H

30 F H H

31 F H H

32 Cl H H

33 Cl H H

34 Cl H H

35 Cl H H

36 Cl H H

37 Cl H H

38 Cl H H

39 Cl H H

40 Cl H H

41 Cl H H

42 Cl H H

43 Cl H H

44 Cl H H

45 F H H

46 H H H

47 H H H

48 H H H

49 H H H

50 H H H

51 H H H

52 H H H

53 H H H

54 H H H

55 H H H

56 H H H

57 H H H

58 H H H

59 CH₃ H H

60 CH₃ H H

61 CH₃ H H

62 CH₃ H H

63 CH₃ H H

64 CH₃ H H

65 CH₃ H H

66 CH₃ H H

67 CH₃ H H

68 CH₃ H H

69 CH₃ H H

70 CH₃ H H

71 CH₃ H H

72 OCH₃ H H

73 OCH₃ H H

74 OCH₃ H H

75 OCH₃ H H

76 OCH₃ H H

77 OCH₃ H H

78 OCH₃ H H

79 OCH₃ H H

80 OCH₃ H H

81 OCH₃ H H

82 OCH₃ H H

83 OCH₃ H H

84 OCH₃ H H

85 N(CH₃)₂ H H

86 N(CH₃)₂ H H

87 N(CH₃)₂ H H

88 N(CH₃)₂ H H

89 N(CH₃)₂ H H

90 N(CH₃)₂ H H

91 N(CH₃)₂ H H

92 N(CH₃)₂ H H

93 N(CH₃)₂ H H

94 N(CH₃)₂ H H

95 N(CH₃)₂ H H

96 N(CH₃)₂ H H

97 N(CH₃)₂ H H

98 F H H

99 CN H H

100 CF₃ H H

101 CF₃ H H

102 CF₃ H H

103 CF₃ H H

104 CF₃ H H

105 CF₃ H H

106 CF₃ H H

107 CF₃ H H

108 CF₃ H H

109 CF₃ H H

110 CF₃ H H

111 CF₃ H H

112 CF₃ H H

113 CN H H

114 CN H H

115 CN H H

116 CN H H

117 CN H H

118 CN H H

119 CN H H

120 CN H H

121 CN H H

122 CN H H

123 CN H H

124 CN H H

125 CONH₂ H H

126 CONH₂ H H

127 CONH₂ H H

128 CN H H

129 CN H H

130 CN H H

131 CN H H

132 CN H H

133 CN H H

134 CN H H

135 CN H H

136 CN H H

137 CN H H

138 F H H

139 Cl H H

140 CN H H

141 H H H

142 CN H H

143 CN H H

144 CN H H

145 F H H

146 Cl H H

147 F H H

148 F H H

149 F H H

150 CN H H

151 CN H H

152 Cl H H

153 Cl H H

154 F H H

155 Cl H H

156 CN H H

Particular compounds of interest, and salts or solvates or stereoisomersthereof, include:

-   Compound 1:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-2-cyclopropylbenzonitrile;-   Compound 2:    N2-(4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)phenyl)-5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine;-   Compound 3:    1-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one;-   Compound 4:    5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methyl-3-(1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine;-   Compound 5:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-9-yl)methylamino)-5-chloropyrimidin-2-ylamino)-2-cyclopropylbenzonitrile;-   Compound 6:    5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methoxy-3-(5-methyl-1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine;-   Compound 7:    5-fluoro-N2-(2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine;-   Compound 8:    5-fluoro-N2-(4-fluoro-3-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine;-   Compound 9:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-2-methylbenzonitrile;-   Compound 10:    3-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)benzonitrile;-   Compound 11:    5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3,5-dimethoxyphenyl)pyrimidine-2,4-diamine;-   Compound 12:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-2-cyclopropyl-4-fluorobenzonitrile;-   Compound 13:    5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-phenylpyrimidine-2,4-diamine;-   Compound 14:    1-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-2-(oxetan-3-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;-   Compound 15:    1-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-2-cyclopropyl-4-methylphenyl)-4-methyl-1H-tetrazol-5(4H)-one;-   Compound 16:    7-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-4-isopropyl-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one;-   Compound 17:    1-(3-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-5-methoxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one;-   Compound 18:    7-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-4-(cyclopropylmethyl)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one;-   Compound 19:    5-fluoro-N2-(3-(trifluoromethyl)-4-morpholinophenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine;-   Compound 20:    5-fluoro-N2-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-7-yl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine;-   Compound 21:    5-fluoro-N2-(3-fluoro-5-methoxyphenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine;-   Compound 22:    5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methoxy-3-(oxazol-5-yl)phenyl)pyrimidine-2,4-diamine;-   Compound 23:    N2-(4-cyclopropyl-2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine;-   Compound 24:    N2-[3-(1,1-dioxo-isothiazolidin-2-yl)-4-fluoro-phenyl]-5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-pyrimidine-2,4-diamine;-   Compound 25:    7-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-4-(3-fluoropropyl)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one;-   Compound 26:    7-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-4-(cyclopropylmethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one;-   Compound 27:    7-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-4-ethyl-2,2-difluoro-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   Compound 28:    N2-(5-(1-methyl-1H-tetrazol-5-yloxy)-4-cyclopropyl-2-fluorophenyl)-5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine;-   Compound 29:    5-fluoro-N2-(3-pentafluorosulfanyl-6-fluoro-phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine;-   Compound 30:    5-fluoro-N2-(3-pentafluorosulfanyl-5-fluoro-phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine;-   Compound 31:    7-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-4-(cyclopropylmethyl)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   Compound 32:    5-chloro-N2-(4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine;-   Compound 33:    5-chloro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methyl-3-(1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine;-   Compound 34:    1-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-chloropyrimidin-2-ylamino)-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one;-   Compound 35:    5-chloro-N2-(4-fluoro-3-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine;-   Compound 36:    5-chloro-N2-(2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine;-   Compound 37:    5-chloro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methoxy-3-(5-methyl-1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine;-   Compound 38:    5-chloro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine;-   Compound 39:    3-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-chloropyrimidin-2-ylamino)benzonitrile;-   Compound 40:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-chloropyrimidin-2-ylamino)-2-methylbenzonitrile;-   Compound 41:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-chloropyrimidin-2-ylamino)-2-cyclopropylbenzonitrile;-   Compound 42:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-chloropyrimidin-2-ylamino)-2-cyclopropyl-4-fluorobenzonitrile;-   Compound 43:    5-chloro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3,5-dimethoxyphenyl)pyrimidine-2,4-diamine;-   Compound 44:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-chloropyrimidin-2-ylamino)benzo[d]oxazol-2(3H)-one;-   Compound 45:    N2-(5-(5-cyclopropyl-1H-tetrazol-1-yl)-2-fluorophenyl)-5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine;-   Compound 46:    N2-(4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine;-   Compound 47:    N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methyl-3-(1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine;-   Compound 48:    1-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)pyrimidin-2-ylamino)-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one;-   Compound 49:    N2-(4-fluoro-3-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine;-   Compound 50:    N2-(2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine;-   Compound 51:    N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methoxy-3-(5-methyl-1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine;-   Compound 52:    N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine;-   Compound 53:    3-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)pyrimidin-2-ylamino)benzonitrile;-   Compound 54:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)pyrimidin-2-ylamino)-2-methylbenzonitrile;-   Compound 55:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)pyrimidin-2-ylamino)-2-cyclopropylbenzonitrile;-   Compound 56:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)pyrimidin-2-ylamino)-2-cyclopropyl-4-fluorobenzonitrile;-   Compound 57:    N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3,5-dimethoxyphenyl)pyrimidine-2,4-diamine;-   Compound 58:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)pyrimidin-2-ylamino)benzo[d]oxazol-2(3H)-one;-   Compound 59:    N2-(4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methylpyrimidine-2,4-diamine;-   Compound 60:    N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methyl-N2-(4-methyl-3-(1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine;-   Compound 61:    1-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methylpyrimidin-2-ylamino)-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one;-   Compound 62:    N2-(4-fluoro-3-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methylpyrimidine-2,4-diamine;-   Compound 63:    N2-(2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methylpyrimidine-2,4-diamine;-   Compound 64:    N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methoxy-3-(5-methyl-1H-tetrazol-1-yl)phenyl)-5-methylpyrimidine-2,4-diamine;-   Compound 65:    N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-5-methylpyrimidine-2,4-diamine;-   Compound 66:    3-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methylpyrimidin-2-ylamino)benzonitrile;-   Compound 67:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methylpyrimidin-2-ylamino)-2-methylbenzonitrile;-   Compound 68:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methylpyrimidin-2-ylamino)-2-cyclopropylbenzonitrile;-   Compound 69:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methylpyrimidin-2-ylamino)-2-cyclopropyl-4-fluorobenzonitrile;-   Compound 70:    N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3,5-dimethoxyphenyl)-5-methylpyrimidine-2,4-diamine;-   Compound 71:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methylpyrimidin-2-ylamino)benzo[d]oxazol-2(3H)-one;-   Compound 72:    N2-(4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methoxypyrimidine-2,4-diamine;-   Compound 73:    N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methoxy-N2-(4-methyl-3-(1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine;-   Compound 74:    1-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methoxypyrimidin-2-ylamino)-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one;-   Compound 75:    N2-(4-fluoro-3-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methoxypyrimidine-2,4-diamine;-   Compound 76:    N2-(2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methoxypyrimidine-2,4-diamine;-   Compound 77:    N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methoxy-N2-(4-methoxy-3-(5-methyl-1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine;-   Compound 78:    N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methoxy-N2-(3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine;-   Compound 79:    3-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methoxypyrimidin-2-ylamino)benzonitrile;-   Compound 80:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methoxypyrimidin-2-ylamino)-2-methylbenzonitrile;-   Compound 81:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methoxypyrimidin-2-ylamino)-2-cyclopropylbenzonitrile;-   Compound 82:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methoxypyrimidin-2-ylamino)-2-cyclopropyl-4-fluorobenzonitrile;-   Compound 83:    N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methoxy-N2-(3,5-dimethoxyphenyl)pyrimidine-2,4-diamine;-   Compound 84:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methoxypyrimidin-2-ylamino)benzo[d]oxazol-2(3H)-one;-   Compound 85:    N2-(4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N5,N5-dimethylpyrimidine-2,4,5-triamine;-   Compound 86:    N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N5,N5-dimethyl-N2-(4-methyl-3-(1H-tetrazol-1-yl)phenyl)pyrimidine-2,4,5-triamine;-   Compound 87:    1-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(dimethylamino)pyrimidin-2-ylamino)-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one;-   Compound 88:    N2-(4-fluoro-3-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N5,N5-dimethylpyrimidine-2,4,5-triamine;-   Compound 89:    N2-(2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N5,N5-dimethylpyrimidine-2,4,5-triamine;-   Compound 90:    N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methoxy-3-(5-methyl-1H-tetrazol-1-yl)phenyl)-N5,N5-dimethylpyrimidine-2,4,5-triamine;-   Compound 91:    N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-N5,N5-dimethylpyrimidine-2,4,5-triamine;-   Compound 92:    3-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(dimethylamino)pyrimidin-2-ylamino)benzonitrile;-   Compound 93:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(dimethylamino)pyrimidin-2-ylamino)-2-methylbenzonitrile;-   Compound 94:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(dimethylamino)pyrimidin-2-ylamino)-2-cyclopropylbenzonitrile;-   Compound 95:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(dimethylamino)pyrimidin-2-ylamino)-2-cyclopropyl-4-fluorobenzonitrile;-   Compound 96:    N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3,5-dimethoxyphenyl)-N5,N5-dimethylpyrimidine-2,4,5-triamine;-   Compound 97:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(dimethylamino)pyrimidin-2-ylamino)benzo[d]oxazol-2(3H)-one;-   Compound 98:    N2-(4,4-dimethyl-4H-5-oxa-1,2,3,9b-tetraaza-cyclopenta[a]naphthalen-8-yl)-5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-pyrimidine-2,4-diamine;-   Compound 99:    4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(4-cyclopropyl-2-fluoro-5-(4,5-dihydro-4-methyl-5-oxotetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile;-   Compound 100:    N2-(4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)phenyl)-5-(trifluoromethyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine;-   Compound 101:    5-(trifluoromethyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methyl-3-(1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine;-   Compound 102:    1-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one;-   Compound 103:    N2-(4-fluoro-3-(5-methyl-1H-tetrazol-1-yl)phenyl)-5-(trifluoromethyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine;-   Compound 104:    N2-(2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-5-(trifluoromethyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine;-   Compound 105:    5-(trifluoromethyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methoxy-3-(5-methyl-1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine;-   Compound 106:    5-(trifluoromethyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine;-   Compound 107:    3-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzonitrile;-   Compound 108:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-methylbenzonitrile;-   Compound 109:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-cyclopropylbenzonitrile;-   Compound 110:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-cyclopropyl-4-fluorobenzonitrile;-   Compound 111:    5-(trifluoromethyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3,5-dimethoxyphenyl)pyrimidine-2,4-diamine;-   Compound 112:    5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzo[d]oxazol-2(3H)-one;-   Compound 113:    4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(4-methoxy-3-(5-methyl-1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile;-   Compound 114:    4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(4-fluoro-3-(5-methyl-1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile;-   Compound 115:    4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile;-   Compound 116:    4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile;-   Compound 117:    4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(4-methyl-3-(1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile;-   Compound 118:    4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile;-   Compound 119:    4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(3-cyano-4-methylphenylamino)pyrimidine-5-carbonitrile;-   Compound 120:    4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(3-cyano-4-cyclopropylphenylamino)pyrimidine-5-carbonitrile;-   Compound 121:    4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(3,5-dimethoxyphenylamino)pyrimidine-5-carbonitrile;-   Compound 122:    4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(3-(5-cyclopropyl-1H-tetrazol-1-yl)-4-fluorophenylamino)pyrimidine-5-carbonitrile;-   Compound 123:    4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(5-(5-cyclopropyl-1H-tetrazol-1-yl)-2-fluorophenylamino)pyrimidine-5-carbonitrile;-   Compound 124:    4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(4-chloro-3-(5-cyclopropyl-1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile;-   Compound 125:    4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(4-methoxy-3-(5-methyl-1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carboxamide;-   Compound 126:    4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(4-fluoro-3-(5-methyl-1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carboxamide;-   Compound 127:    4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carboxamide;-   Compound 128:    2-((2-fluoro-4-hydroxy-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile;-   Compound 129:    2-((2-fluoro-4-(2-methoxyethoxy)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile;-   Compound 130:    2-((2-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)-4-((3-methyloxetan-3-yl)methoxy)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile;-   Compound 131:    2-((4-((1,4-dioxan-2-yl)methoxy)-2-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile;-   Compound 132:    2-((4-(2,3-dihydroxypropoxy)-2-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile;-   Compound 133:    2-((2-fluoro-4-(2-(2-methoxyethoxyl)ethoxy)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile;-   Compound 134:    2-((2-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)-4-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propoxy)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile;-   Compound 135:    2-((2-fluoro-4-(2-hydroxyethoxy)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile;-   Compound 136:    2-((2-fluoro-4-(2-hydroxypropoxy)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile;-   Compound 137:    2-((2-fluoro-4-(2-hydroxyethoxy-1,1,2,2-d4)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile;-   Compound 138:    2-(4-((5-fluoro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-2-(1H-tetrazol-1-yl)phenoxy)ethan-1-ol;-   Compound 139:    2-(4-((5-chloro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-2-(1H-tetrazol-1-yl)phenoxy)ethan-1-ol;-   Compound 140:    2-((4-(2-hydroxyethoxy)-3-(1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile;-   Compound 141:    2-(4-((4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-2-(1H-tetrazol-1-yl)phenoxy)ethan-1-ol;-   Compound 142:    2-((2-fluoro-4-((S)-2-hydroxypropoxy)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile;-   Compound 143:    2-((2-fluoro-4-((R)-2-hydroxypropoxy)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile;-   Compound 144: 2-((3-cyano-4-(2-hydroxypropoxy)phenyl)amino)-4-((((1    S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile;-   Compound 145:    5-((5-fluoro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-2-(2-hydroxypropoxy)benzonitrile;-   Compound 146:    1-(5-((5-chloro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-4-fluoro-2-hydroxyphenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one;-   Compound 147:    1-(5-((5-fluoro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-4-fluoro-2-hydroxyphenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one;-   Compound 148:    1-(4-fluoro-5-((5-fluoro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-2-((1-hydroxy-2-methylpropan-2-yl)oxy)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one;-   Compound 149:    1-(4-fluoro-5-((5-fluoro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-2-((S)-2-hydroxypropoxy)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one;-   Compound 150: ethyl    2-(4-((5-cyano-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-5-fluoro-2-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenoxy)-2-methylpropanoate;-   Compound 151:    2-((2-fluoro-4-((1-hydroxy-2-methylpropan-2-yl)oxy)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile;-   Compound 152:    1-(5-((5-chloro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-4-fluoro-2-((S)-2-hydroxypropoxy)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one;-   Compound 153:    1-(5-((5-chloro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-4-fluoro-2-((1-hydroxy-2-methylpropan-2-yl)oxy)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one;-   Compound 154:    1-(4-fluoro-5-((5-fluoro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-2-(2-hydroxy-2-methylpropoxy)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one;-   Compound 155:    1-(5-((5-chloro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-4-fluoro-2-(2-hydroxy-2-methylpropoxy)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one;    and-   Compound 156:    2-((2-fluoro-4-(2-hydroxy-2-methylpropoxy)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile.

Aspects of the present disclosure also include a compound according tothe formula:

wherein

Z¹ is OR¹⁷, —NR¹⁷R¹⁸ or X;

Z² is H, or Z¹ and Z² together form an oxo, ═NR¹⁹ or ═NNR²⁰R²¹;

R¹⁷ is H, alkyl, substituted alkyl, acyl, acylamino, —SO₂-alkyl or—SO₂-aryl;

R¹⁸ is H, alkyl, substituted alkyl, acyl, acylamino, —SO₂-alkyl,—SO₂-aryl, aryl, substituted aryl, heteroaryl, or substitutedheteroaryl;

X is halo or azido; and

R¹⁹, R²⁰ and R²¹ are each independently selected from alkyl, substitutedalkyl, aryl substituted aryl, heteroaryl and substituted heteroaryl.

In certain embodiments of formula (V), the compound is optically active.In certain embodiments of formula (V), there is an enantiomeric excessof 90% or more. In certain embodiments of formula (V), there is anenantiomeric excess of 95% or more. In certain embodiments of formula(V), there is an enantiomeric excess of 99% or more.

In certain embodiments, in formula (V), R¹⁸ comprises the formula

wherein R¹¹ is selected from hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy,amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen,acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, sulfide, substituted sulfide, and SF₅;

Y² is selected from hydrogen and alkyl; and

Ar¹ is selected from aryl, substituted aryl, heteroaryl, and substitutedheteroaryl.

In certain embodiments, the compound of formula (V) comprises theformula

In certain embodiments, the compound of formula (V) comprises theformula

In certain embodiments, the compound of formula (V) comprises theformula

In certain embodiments, the compound of formula (V) comprises theformula

In certain embodiments, the compound of formula (V) comprises theformula

In certain embodiments, the compound of formula (V) comprises theformula

In certain embodiments, the compound of formula (V) comprises theformula

Aspects of the present disclosure also include a compound according tothe formula:

wherein

R¹¹ is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy, amino,substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl,aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,sulfide, substituted sulfide, and SF₅; and

Y¹ is selected from hydrogen and alkyl.

In formula (VI), G is halogen or —NY²Ar¹. In certain embodiments, G ishalogen. In certain embodiments, G is —NY²Ar¹. In certain embodiments,Y² is selected from hydrogen and alkyl. In certain embodiments, Ar¹ isselected from aryl, substituted aryl, heteroaryl, and substitutedheteroaryl. In certain embodiments, Ar¹ is aryl or substituted aryl. Incertain embodiments, Ar¹ is heteroaryl or substituted heteroaryl.

In certain embodiments, a compound of formula (VI) is of the formula:

wherein

R¹¹ is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy, amino,substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl,aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,sulfide, substituted sulfide, and SF₅; and

Y¹ is selected from hydrogen and alkyl.

In certain embodiments, a compound of formula (VI) is of the formula:

wherein

R¹¹ is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy, amino,substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl,aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,sulfide, substituted sulfide, and SF₅;

Y¹ is selected from hydrogen and alkyl; and

H¹ and H² are each hydrogen.

In certain embodiments, H¹ and H² are hydrogen with cis relativeconfiguration. In certain embodiments, H¹ and H² are hydrogen with transrelative configuration.

In certain embodiments, R¹¹ in formulae (V) and (VI) is as describedabove in relation to formulae (I)-(IV).

The compounds described also include isotopically labeled compoundswhere one or more atoms have an atomic mass different from the atomicmass conventionally found in nature. Examples of isotopes that may beincorporated into the compounds disclosed herein include, but are notlimited to, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, etc. Thus, thedisclosed compounds may be enriched in one or more of these isotopesrelative to the natural abundance of such isotope. By way of example,deuterium (²H) has a natural abundance of about 0.015%. Accordingly, forapproximately every 6,500 hydrogen atoms occurring in nature, there isone deuterium atom. Specifically contemplated herein are compoundsenriched in deuterium at one or more positions. Thus, deuteriumcontaining compounds of the disclosure have deuterium at one or morepositions (as the case may be) in an abundance of greater than 0.015%.

The present disclosure also provides pharmaceutical compositions thatinclude a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound of formula I-IV or a pharmaceuticallyacceptable salt or solvate or stereoisomer thereof.

A disclosed compound can be administered alone, as the sole activepharmaceutical agent, or in combination with one or more additionalcompounds of formula I-IV or in conjunction with other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are administered simultaneously or atdifferent times, or the therapeutic agents can be administered togetheras a single composition combining two or more therapeutic agents. Thus,the pharmaceutical compositions disclosed herein containing a compoundof formula I-IV optionally include other therapeutic agents.Accordingly, certain embodiments are directed to such pharmaceuticalcompositions, where the composition further includes a therapeuticallyeffective amount of an agent selected as is known to those of skill inthe art.

The subject compounds can inhibit a protein kinase C (PKC) activity.Accordingly, the compounds are useful for treating a disease or disorderthat is mediated through the activity of a PKC activity in a subject.Also, the compounds are useful for treating a disease or disorder thatis associated with the activation of T-cells in a subject.

The present disclosure provides a method of treating an inflammatorydisease in a subject. In certain embodiments, the method includesadministering to the subject (e.g., patient) a compound of formula I-IVor a salt or solvate or stereoisomer thereof.

The present disclosure also provides a method of treating an autoimmunedisease in a subject. In certain embodiments, the method includesadministering to the subject (e.g., patient) a compound of formula I-IVor a salt or solvate or stereoisomer thereof.

The present disclosure also provides a method of treating an oculardisease or disorder involving inflammatory and/or neovascular events.

The present disclosure also provides a method of treating diseases orconditions of interest including, but are not limited to,atherosclerosis, vascular occlusion due to vascular injury, angioplasty,restenosis, obesity, syndrome X, impaired glucose tolerance, polycysticovary syndrome, hypertension, heart failure, chronic obstructivepulmonary disease, CNS diseases, Alzheimer disease, amyotrophic lateralsclerosis, bipolar disease, cancer, infectious disease, AIDS, septicshock, adult respiratory distress syndrome, ischemia/reperfusion injury,myocardial infarction, stroke, gut ischemia, renal failure, hemorrhageshock, and traumatic shock, and traumatic brain injury. In certainembodiments, the present compounds are useful in treating musclediseases or disorders, including inflammatory muscle disease anddystrophic disorders, such as Duchenne muscular dystrophy and myotonicmuscular dystrophy.

The present disclosure also provides a method of treating diseases orconditions of interest including, but are not limited to, T-cellmediated acute or chronic inflammatory diseases or disorders orautoimmune diseases, rheumatoid arthritis, osteoarthritis, systemiclupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis,myasthenia gravis, diabetes type I or II and the disorders associatedtherewith, transplant rejection, graft versus host disease, respiratorydiseases, asthma, inflammatory lung injury, inflammatory liver injury,inflammatory glomerular injury, cutaneous manifestations ofimmunologically-mediated disorders or illnesses, inflammatory andhyperproliferative skin diseases, psoriasis, atopic dermatitis, allergiccontact dermatitis, irritant contact dermatitis and further eczematousdermatitises, seborrhoeic dermatitis, inflammatory eye diseases,Sjoegren's syndrome, keratoconjunctivitis, uveitis, inflammatory boweldisease, Crohn's disease or ulcerative colitis, Guillain-Barre syndrome,and allergies.

The subject compounds can be used for treating a cell proliferativedisorder. The present disclosure also provides a method of treatingdiseases or conditions of interest including, but are not limited to,hematopoietic neoplasm, lymphoid neoplasm, T cell neoplasm,T-lymphoblastic leukemia, B cell neoplasm, B-lymphoblastic leukemia,Burkitt's lymphoma, myeloid neoplasm, myeloproferative disease, chronicmyelogenous leukemia (CML), myelodysplastic disease, chronicmyelomonocytic leukemia, myelodysplastic syndrome, and acute myeloidleukemia.

Since embodiments of the subject compounds possess PKC inhibitoryproperties, such compounds are also useful as research tools.Accordingly, the disclosure also provides for a method for using acompound of formula I-IV or a salt or solvate or stereoisomer thereof asa research tool for studying a biological system or sample, or fordiscovering new chemical compounds having PKC inhibitory properties.

The embodiments are also directed to a compound of formula I-IV or asalt or solvate or stereoisomer thereof, for use in therapy or as amedicament.

Additionally, the embodiments are directed to the use of a compound offormula I-IV or a salt or solvate or stereoisomer thereof, for themanufacture of a medicament; for example, for the manufacture of amedicament for the inhibition of protein kinase C (PKC) activity. Theembodiments are also directed to the use of a compound of formula I-IVor a salt or solvate or stereoisomer thereof for the manufacture of amedicament for the treatment of a disease or disorder mediated orsustained through the activity of PKC activity. The embodiments are alsodirected to the use of a compound of formula I-IV or a salt or solvateor stereoisomer thereof for the manufacture of a medicament for thetreatment of a disease or disorder associated with the activation ofT-cells. Diseases or conditions of interest include, but are not limitedto, an inflammatory disease, an immunological disorder, an autoimmunedisease, an ocular disease or disorder involving inflammatory and/orneovascular events, organ and bone marrow transplant rejection, acute orchronic inflammation, allergies, contact dermatitis, psoriasis,rheumatoid arthritis, multiple sclerosis, type I diabetes, type IIdiabetes, inflammatory bowel disease, Guillain-Barre syndrome, Crohn'sdisease, ulcerative colitis, graft versus host disease, and lupuserythematosus.

The embodiments of the present disclosure are also directed to the useof a compound of formula I-IV or a salt or solvate or stereoisomerthereof for the manufacture of a medicament for the treatment of a cellproliferative disorder. Diseases or conditions of interest include, butare not limited to, hematopoietic neoplasm, lymphoid neoplasm, T cellneoplasm, T-lymphoblastic leukemia, B cell neoplasm, B-lymphoblasticleukemia, Burkitt's lymphoma, myeloid neoplasm, myeloproferativedisease, chronic myelogenous leukemia (CML), myelodysplastic disease,chronic myelomonocytic leukemia, myelodysplastic syndrome, acute myeloidleukemia.

General Synthetic Procedures

Many general references providing commonly known chemical syntheticschemes and conditions useful for synthesizing the disclosed compoundsare available (see, e.g., Smith and March, March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, Fifth Edition,Wiley-Interscience, 2001; or Vogel, A Textbook of Practical OrganicChemistry, Including Qualitative Organic Analysis, Fourth Edition, NewYork: Longman, 1978).

Compounds as described herein can be purified by any purificationprotocol known in the art, including chromatography, such as HPLC,preparative thin layer chromatography, flash column chromatography andion exchange chromatography. Any suitable stationary phase can be used,including normal and reversed phases as well as ionic resins. In certainembodiments, the disclosed compounds are purified via silica gel and/oralumina chromatography. See, e.g., Introduction to Modern LiquidChromatography, 2nd Edition, ed. L. R. Snyder and J. J. Kirkland, JohnWiley and Sons, 1979; and Thin Layer Chromatography, ed E. Stahl,Springer-Verlag, New York, 1969.

During any of the processes for preparation of the subject compounds, itmay be necessary and/or desirable to protect sensitive or reactivegroups on any of the molecules concerned. This may be achieved by meansof conventional protecting groups as described in standard works, suchas J. F. W. McOmie, “Protective Groups in Organic Chemistry”, PlenumPress, London and New York 1973, in T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis”, Third edition, Wiley, New York1999, in “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer),Academic Press, London and New York 1981, in “Methoden der organischenChemie”, Houben-Weyl, 4^(th) edition, Vol. 15/1, Georg Thieme Verlag,Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, “Aminosauren, Peptide,Proteine”, Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982,and/or in Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharide andDerivate”, Georg Thieme Verlag, Stuttgart 1974. The protecting groupsmay be removed at a convenient subsequent stage using methods known fromthe art.

The subject compounds can be synthesized via a variety of differentsynthetic routes using commercially available starting materials and/orstarting materials prepared by conventional synthetic methods. Suitableexamples of methods that can be adapted to synthesize the2,4-pyrimidinediamine compounds and prodrugs disclosed herein are foundin U.S. Pat. No. 5,958,935, the disclosure of which is incorporatedherein by reference. Specific examples describing the synthesis ofvarious 2,4-pyrimidinediamine compounds and prodrugs, as well asintermediates therefore, are described in the U.S. ApplicationPublication No. 2004/0029902, the disclosure of which are incorporatedherein by reference. Suitable examples of methods that can be routinelyused and/or adapted to synthesize active 2,4-pyrimidinediamine compoundscan also be found in WO 03/063794, U.S. application Ser. No. 10/631,029,filed Jul. 29, 2003, WO2004/014382, U.S. Application Publication No.2005/0234049, and WO2005/016893, the disclosures of each of which areincorporated herein by reference. All of the compounds described herein(including prodrugs) can be prepared by adaptation of these methods.

Exemplary synthetic methods for the 2,4-substituted pyrimidinediaminesdescribed herein are described below. Those of skill in the art willalso be able to readily adapt these methods for the synthesis ofspecific 2,4-substituted pyrimidinediamines as described herein.

A variety of examples of synthetic routes that can be used to synthesizethe 2,4-pyrimidinediamine compounds disclosed herein are described inthe schemes below. These methods can be adapted to synthesize the2,4-pyrimidinediamine compounds and prodrugs described herein.

Synthesis of Compounds

In certain embodiments, the compounds can be synthesized fromsubstituted or unsubstituted uracils as illustrated in Scheme 1, below:

In Scheme 1, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, Y¹, Y², and Q are as setforth hereinbefore.

According to Scheme 1, uracil A-1 is dihalogenated at the 2- and4-positions using a standard dehydrating-halogenating agent such asPOCl₃ (phosphorus oxychloride) (or other standard halogenating agent) toyield 2,4 dichloropyrimidine A-2. Depending upon the substituents inpyrimidinediamine A-2, the chloride at the C4 position is more reactivetowards nucleophiles than the chloride at the C2 position. Thisdifferential reactivity can be exploited by first reacting 2,4dichloropyrimidine A-2 with one equivalent of amine A-3, yielding4N-substituted-2-chloro-4-pyrimidineamine A-4, followed by one or moreequivalents of amine A-5 to yield a 2,4-pyrimidinediamine derivativeA-6.

Typically, the C4 halide is more reactive towards nucleophiles, asillustrated in the scheme. However, as will be recognized by skilledartisans, the identity of the substituent may alter this reactivity. Forexample, when the substituent is trifluoromethyl, a 50:50 mixture of4N-substituted-4-pyrimidineamine A-4 and the corresponding2N-substituted-2-pyrimidineamine is obtained. The regioselectivity ofthe reaction can also be controlled by adjusting the solvent and othersynthetic conditions (such as temperature), as is well-known in the art.

In certain embodiments, to couple compounds with an electrophilicleaving group, such as halides or pseudohalides, and compounds with anamino group, nucleophilic aromatic substitution can be used. Forexample, a halogen substituent on Compound A-2 and the amino group onCompound A-3 can react. Also for example, a halogen substituent onCompound A-4 and the amino group on Compound A-5 can react. Conditionsfor nucleophilic aromatic substitution include the compounds reacting ina polar aprotic solvent or polar protic solvent. Suitable solventsinclude alcohols (such as isopropanol, methanol, ethanol), formic acid,dimethylsulfoxide, dimethylformamide, dioxane, and tetrahydrofuran. Thereaction can be run at room temperature or can be heated.

In certain embodiments, to couple compounds with an electrophilicleaving group, such as halides or pseudohalides, and aryl compounds withan amino group, a coupling reaction, such as a Buchwald couplingreaction, can be used. The Buchwald coupling reaction involvespalladium-catalyzed synthesis of aryl amines. Starting materials arearyl halides or pseudohalides (for example, triflates) and primary orsecondary amines. Such reaction can be performed using a variety ofmethods well known in the art and specific examples can be had byreference to the Examples hereunder described.

A specific embodiment of Scheme 1 utilizing 5-fluorouracil (Aldrich#32,937-1) as a starting material is illustrated in Scheme 2, below.

In Scheme 2, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, Y¹, Y², and Q are as setforth hereinbefore.

Asymmetric 2N,4N-disubstituted-5-fluoro-2,4-pyrimidinediamine A-10 canbe obtained by reacting 2,4-dichloro-5-fluoropyrimidine A-8 with oneequivalent of amine A-3 (to yield2-chloro-N4-substituted-5-fluoro-4-pyrimidineamine A-9) followed by oneor more equivalents of amine A-5.

In certain embodiments, chloro derivatives of the compounds can besynthesized as illustrated in Scheme 3, below:

In Scheme 3, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, Y¹, Y², and Q are as set forthhereinbefore.

Asymmetric 2N,4N-disubstituted-5-chloro-2,4-pyrimidinediamine A-15 canbe obtained by reacting 2,5-dichloropyrimidin-4-ol A-12 with oneequivalent of amine A-5 (to yield N2-substituted-5-chloro-pyrimidin-4-olA-13). The hydroxy group of Compound A-13 is converted to a chloro groupto yield Compound A-14, followed by reaction with one or moreequivalents of amine A-3. Conversion of the hydroxy group to the chlorogroup can be accomplished with a dehydrating-halogenating agent such asPOCl₃ (phosphorus oxychloride) (or other standard halogenating agent).

Uracil Starting Materials and Intermediates

The uracil A-1 and A-7 starting materials can be purchased fromcommercial sources or prepared using standard techniques of organicchemistry. Commercially available uracils that can be used as startingmaterials in the schemes disclosed herein include, but are not limitedto, uracil (Aldrich #13,078-8; CAS Registry 66-22-8); 5-chlorouracil(Aldrich #224588; CAS Registry 1820-81-1); 5-bromouracil (Aldrich#85,247-3; CAS Registry 51-20-7); 5-fluorouracil (Aldrich #85,847-1; CASRegistry 51-21-8); 5-iodouracil (Aldrich #85,785-8; CAS Registry696-07-1); 5-nitrouracil (Aldrich #85,276-7; CAS Registry 611-08-5);5-methyluracil (thymine, Aldrich #T0376; CAS Registry 65-71-4);5-(trifluoromethyl)-uracil (Aldrich #22,327-1; CAS Registry 54-20-6);5-cyanouracil (Aldrich #AMS000822). Additional 5-substituted uracils areavailable from General Intermediates of Canada, Inc., Edmonton, CAand/or Interchim, Cedex, France, or can be prepared using standardtechniques. Various textbook references teaching suitable syntheticmethods are provided infra.

Pyrimidine Starting Materials and Intermediates

Pyrimidines, such as A-11 can be purchased from commercial sources or,alternatively, can be synthesized utilizing standard techniques.Commercially available pyrimidines that can be used as startingmaterials in the schemes disclosed herein include, but are not limitedto, 2,4,5-trichloropyrimidine (Aldrich #652032; CAS Registry 5750-76-5).

Amino Starting Materials and Intermediates

Amines, such as A-3 and A-5 can be purchased from commercial sources or,alternatively, can be synthesized utilizing standard techniques. Forexample, suitable amines can be synthesized from nitro precursors usingstandard chemistry. See also Vogel, 1989, Practical Organic Chemistry,Addison Wesley Longman, Ltd. and John Wiley & Sons, Inc. For example,amines A-5 can be prepared as described in WO 2010/090875, WO2010/083207, WO 2011/068898 and WO 2012/012619, the disclosures of eachof which are incorporated herein by reference.

In certain embodiments, Compound A-3 can be synthesized as illustratedin Schemes 4 and 5, below.

Referring to Scheme 4, thiolactam B-2 can be prepared by conjugateaddition of piperidine-2-thione B-1 to ethyl acrylate. Compound B-3 canbe prepared as a single geometric isomer by reacting Compound B-2 withbromoacetonitrile in the presence of triphenylphosphine andtriethylamine. Selective reduction of the ester group of Compound B-3affords the alcohol (Compound B-4). Suitable conditions for reduction ofthe ester group include reaction with lithium aluminum hydride, and thelike. Tosylate B-5 can be prepared under standard conditions (e.g., NaH,p-TsCl). Subsequent intramolecular mucleophilic displacement of CompoundB-5 affords Compound B-6.

Compound B-6 may serve as an intermediate precursor for thedisatereomeric amines (which includes Compound A-3), as shown in Scheme5 below.

Referring to Scheme 5, intermediate Compound B-6 can be preferentiallyconverted to the cis-hydrogenated cyanoquinolizidine B-7 by catalytichydrogenation. Alternatively, reduction of Compound B-6 with sodiumcyanoborohydride affords an excess of the trans-cyanoquinolizidine B-8.The nitrile group on Compounds B-7 and B-8 can be reduced to afford(±)-lupinamine B-9 and (±)-epilupinamine B-10, respectively. Suitableconditions for reduction of the nitrile group in Compounds B-7 and B-8include reaction with a catalyst, such as, but not limited to,nickel-aluminum alloy, or reaction with a reducing agent, such as, butnot limited to, lithium aluminum hydride, and the like. Additionaldetails of the reactions described in Schemes 4 and 5 may be found inMichael, J. P., and Jungmann, C. M., Tetrahedron, vol. 48, no. 46, pp.10211-20220 (1992).

The stereoisomers of Compound A-3 can be isolated by procedures known tothose skilled in the art. The individual stereoisomers may be obtained,for instance, by a resolution technique or by chromatography techniques(e.g., silica gel chromatography, chiral chromatography, etc.).

Although many of the synthetic schemes discussed above do not illustratethe use of protecting groups, skilled artisans will recognize that insome instances certain substituents may include functional groupsrequiring protection. The exact identity of the protecting group usedwill depend upon, among other things, the identity of the functionalgroup being protected and the reaction conditions used in the particularsynthetic scheme, and will be apparent to those of skill in the art.Guidance for selecting protecting groups, their attachment and removalsuitable for a particular application can be found, for example, inGreene & Wuts, supra.

Prodrugs as described herein can be prepared by routine modification ofthe above-described methods. Alternatively, such prodrugs can beprepared by reacting a suitably protected 2,4-pyrimidinediamine with asuitable progroup. Conditions for carrying out such reactions and fordeprotecting the product to yield prodrugs as described herein arewell-known.

Various references teaching methods useful for synthesizing pyrimidinesgenerally, as well as starting materials described in the Schemes above,are known in the art. For specific guidance, the reader is referred toBrown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16 (Weissberger, A., Ed.), 1962, IntersciencePublishers, (A Division of John Wiley & Sons), New York (“Brown I”);Brown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16, Supplement I (Weissberger, A. and Taylor, E. C.,Ed.), 1970, Wiley-Interscience, (A Division of John Wiley & Sons), NewYork (Brown II”); Brown, D. J., “The Pyrimidines”, in The Chemistry ofHeterocyclic Compounds, Volume 16, Supplement II (Weissberger, A. andTaylor, E. C., Ed.), 1985, An Interscience Publication (John Wiley &Sons), New York (“Brown III”); Brown, D. J., “The Pyrimidines” in TheChemistry of Heterocyclic Compounds, Volume 52 (Weissberger, A. andTaylor, E. C., Ed.), 1994, John Wiley & Sons, Inc., New York, pp. 1-1509(Brown IV”); Kenner, G. W. and Todd, A., in Heterocyclic Compounds,Volume 6, (Elderfield, R. C., Ed.), 1957, John Wiley, New York, Chapter7 (pyrimidines); Paquette, L. A., Principles of Modern HeterocyclicChemistry, 1968, W. A. Benjamin, Inc., New York, pp. 1-401 (uracilsynthesis pp. 313, 315; pyrimidinediamine synthesis pp. 313-316; aminopyrimidinediamine synthesis pp. 315); Joule, J. A., Mills, K. and Smith,G. F., Heterocyclic Chemistry, 3rd Edition, 1995, Chapman and Hall,London, UK, pp. 1-516; Vorbrüggen, H. and Ruh-Pohlenz, C., Handbook ofNucleoside Synthesis, John Wiley & Sons, New York, 2001, pp. 1-631(protection of pyrimidines by acylation pp. 90-91; silylation ofpyrimidines pp. 91-93); Joule, J. A., Mills, K. and Smith, G. F.,Heterocyclic Chemistry, 4th Edition, 2000, Blackwell Science, Ltd,Oxford, UK, pp. 1-589; and Comprehensive Organic Synthesis, Volumes 1-9(Trost, B. M. and Fleming, I., Ed.), 1991, Pergamon Press, Oxford, UK.

The embodiments are also directed to processes and novel intermediatesuseful for preparing compounds of formula I-IV or a salt or solvate orstereoisomer thereof.

Accordingly, the present disclosure provides a method for making acompound according to the formula

wherein

R¹¹ is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy, amino,substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl,aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,sulfide, substituted sulfide, and SF₅; and

Y¹ is selected from hydrogen and alkyl.

In certain embodiments, the method includes contacting a compound of theformula

with a compound of the formula:

Aspects of the present disclosure include a method for making a compoundaccording to the formula

wherein

R¹¹ is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy, amino,substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl,aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,sulfide, substituted sulfide, and SF₅;

Y¹ and Y² are independently selected from hydrogen and alkyl; and

Ar¹ is selected from aryl, substituted aryl, heteroaryl, and substitutedheteroaryl.

In certain embodiments, the method includes contacting a compound of theformula

wherein X¹ is a halogen;

-   -   with a compound of the formula HNY²Ar¹. R¹¹, Y¹, Y² and Ar¹ are        as described hereinbefore.

In certain embodiments, in the above methods, the method furtherincludes separating isomers with a resolution technique. In certainembodiments, in the above methods, the method further includesseparating isomers with chiral chromatography. In certain embodiments,the disclosure provides a method for preparing an aptically activecompound, for example as shown in Schemes 4 and 5 above.

In some embodiments, the above methods further include the step offorming a salt of a compound of formula I-IV. Embodiments are directedto the other processes described herein, and to the product prepared byany of the processes described herein.

Pharmaceutical Compositions

In certain embodiments, the disclosed compounds are useful for theinhibition of PKC activity and the treatment of a disease or disorderthat is mediated through the activity of a PKC activity. Accordingly,pharmaceutical compositions comprising at least one disclosed compoundare also described herein.

A pharmaceutical composition that includes a subject compound may beadministered to a patient alone, or in combination with othersupplementary active agents. The pharmaceutical compositions may bemanufactured using any of a variety of processes, including, but notlimited to, conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping, lyophilizing, andthe like. The pharmaceutical composition can take any of a variety offorms including, but not limited to, a sterile solution, suspension,emulsion, lyophilisate, tablet, pill, pellet, capsule, powder, syrup,elixir or any other dosage form suitable for administration.

A subject compound may be administered to a subject using any convenientmeans capable of resulting in the desired reduction in disease conditionor symptom. Thus, a subject compound can be incorporated into a varietyof formulations for therapeutic administration. More particularly, asubject compound can be formulated into pharmaceutical compositions bycombination with appropriate pharmaceutically acceptable carriers ordiluents, and may be formulated into preparations in solid, semi-solid,liquid or gaseous forms, such as tablets, capsules, powders, granules,ointments, solutions, suppositories, injections, inhalants, aerosols,and the like

Formulations for pharmaceutical compositions are described in, forexample, Remington's Pharmaceutical Sciences, by E. W. Martin, MackPublishing Co., Easton, Pa., 19th Edition, 1995, which describesexamples of formulations (and components thereof) suitable forpharmaceutical delivery of disclosed compounds. Pharmaceuticalcompositions that include at least one of the subject compounds can beformulated for use in human or veterinary medicine. Particularformulations of a disclosed pharmaceutical composition may depend, forexample, on the mode of administration and/or on the location of thesubject to be treated. In some embodiments, formulations include apharmaceutically acceptable carrier in addition to at least one activeingredient, such as a subject compound. In other embodiments, othermedicinal or pharmaceutical agents, for example, with similar, relatedor complementary effects on the disease or condition being treated canalso be included as active ingredients in a pharmaceutical composition.

Pharmaceutically acceptable carriers useful for the disclosed methodsand compositions may depend on the particular mode of administrationbeing employed. For example, parenteral formulations may includeinjectable fluids, such as, but not limited to, pharmaceutically andphysiologically acceptable fluids such as water, physiological saline,balanced salt solutions, aqueous dextrose, glycerol or the like as avehicle. For solid compositions (e.g., powder, pill, tablet, or capsuleforms), non-toxic solid carriers can include, for example,pharmaceutical grades of mannitol, lactose, starch, or magnesiumstearate. In addition to biologically neutral carriers, pharmaceuticalcompositions to be administered can optionally contain minor amounts ofnon-toxic auxiliary substances (e.g., excipients), such as wetting oremulsifying agents, preservatives, and pH buffering agents and the like;for example, sodium acetate or sorbitan monolaurate. Other examples ofexcipients include, nonionic solubilizers, such as cremophor, orproteins, such as human serum albumin or plasma preparations.

Some examples of materials which can serve aspharmaceutically-acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) water (e.g., pyrogen-free water); (17) isotonic saline; (18)Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21)polyesters, polycarbonates and/or polyanhydrides; and (22) othernon-toxic compatible substances employed in pharmaceutical formulations.

The disclosed pharmaceutical compositions may be formulated as apharmaceutically acceptable salt of a disclosed compound.Pharmaceutically acceptable salts are non-toxic salts of a free baseform of a compound that possesses the desired pharmacological activityof the free base. These salts may be derived from inorganic or organicacids. Non-limiting examples of suitable inorganic acids arehydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid,hydroiodic acid, and phosphoric acid. Non-limiting examples of suitableorganic acids are acetic acid, propionic acid, glycolic acid, lacticacid, pyruvic acid, malonic acid, succinic acid, malic acid, maleicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, methylsulfonic acid, salicylic acid, formic acid, trichloroacetic acid,trifluoroacetic acid, gluconic acid, asparagic acid, aspartic acid,benzenesulfonic acid, para-toluenesulfonic acid, naphthalenesulfonicacid, and the like. In certain embodiments, the pharmaceuticallyacceptable salt includes formic acid. In certain embodiments, thepharmaceutically acceptable salt includes trifluoroacetic acid. Othersuitable pharmaceutically acceptable salts are found in Remington'sPharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton,Pa., 1985. A pharmaceutically acceptable salt may also serve to adjustthe osmotic pressure of the composition.

A subject compound can be used alone or in combination with appropriateadditives to make tablets, powders, granules or capsules, for example,with conventional additives, such as lactose, mannitol, corn starch orpotato starch; with binders, such as crystalline cellulose, cellulosederivatives, acacia, corn starch or gelatins; with disintegrators, suchas corn starch, potato starch or sodium carboxymethylcellulose; withlubricants, such as talc or magnesium stearate; and if desired, withdiluents, buffering agents, moistening agents, preservatives andflavoring agents. Such preparations can be used for oral administration.

A subject compound can be formulated into preparations for injection bydissolving, suspending or emulsifying the compound in an aqueous ornonaqueous solvent, such as vegetable or other similar oils, syntheticaliphatic acid glycerides, esters of higher aliphatic acids or propyleneglycol; and if desired, with conventional additives such assolubilizers, isotonic agents, suspending agents, emulsifying agents,stabilizers and preservatives. The preparation may also be emulsified orthe active ingredient encapsulated in liposome vehicles. Formulationssuitable for injection can be administered by an intravitreal,intraocular, intramuscular, subcutaneous, sublingual, or other route ofadministration, e.g., injection into the gum tissue or other oraltissue. Such formulations are also suitable for topical administration.

In some embodiments, a subject compound can be delivered by a continuousdelivery system. The term “continuous delivery system” is usedinterchangeably herein with “controlled delivery system” and encompassescontinuous (e.g., controlled) delivery devices (e.g., pumps) incombination with catheters, injection devices, and the like, a widevariety of which are known in the art.

A subject compound can be utilized in aerosol formulation to beadministered via inhalation. A subject compound can be formulated intopressurized acceptable propellants such as dichlorodifluoromethane,propane, nitrogen and the like.

Furthermore, a subject compound can be made into suppositories by mixingwith a variety of bases such as emulsifying bases or water-solublebases. A subject compound can be administered rectally via asuppository. The suppository can include vehicles such as cocoa butter,carbowaxes and polyethylene glycols, which melt at body temperature, yetare substantially solid at room temperature.

The term “unit dosage form,” as used herein, refers to physicallydiscrete units suitable as unitary dosages for human and animalsubjects, each unit containing a predetermined quantity of a subjectcompound calculated in an amount sufficient to produce the desiredeffect in association with a pharmaceutically acceptable diluent,carrier or vehicle. The specifications for a subject compound depend onthe particular compound employed and the effect to be achieved, and thepharmacodynamics associated with each compound in the host.

The dosage form of a disclosed pharmaceutical composition may bedetermined by the mode of administration chosen. For example, inaddition to injectable fluids, topical or oral dosage forms may beemployed. Topical preparations may include eye drops, ointments, spraysand the like. Oral formulations may be liquid (e.g., syrups, solutionsor suspensions), or solid (e.g., powders, pills, tablets, or capsules).Methods of preparing such dosage forms are known, or will be apparent,to those skilled in the art.

Certain embodiments of the pharmaceutical compositions that include asubject compound may be formulated in unit dosage form suitable forindividual administration of precise dosages. The amount of activeingredient administered may depend on the subject being treated, theseverity of the affliction, and the manner of administration, and isknown to those skilled in the art. In certain instances, the formulationto be administered contains a quantity of the compounds disclosed hereinin an amount effective to achieve the desired effect in the subjectbeing treated.

Each therapeutic compound can independently be in any dosage form, suchas those described herein, and can also be administered in various ways,as described herein. For example, the compounds may be formulatedtogether, in a single dosage unit (that is, combined together in oneform such as capsule, tablet, powder, or liquid, etc.) as a combinationproduct. Alternatively, when not formulated together in a single dosageunit, an individual subject compound may be administered at the sametime as another therapeutic compound or sequentially, in any orderthereof.

Methods of Administration

The subject compounds can inhibit a protein kinase C (PKC) activity.Accordingly, the subject compounds are useful for treating a disease ordisorder that is mediated through the activity of a PKC activity in asubject. In certain embodiments, the subject compounds are useful fortreating a disease or disorder that is associated with the activation ofT-cells in a subject.

The route of administration may be selected according to a variety offactors including, but not limited to, the condition to be treated, theformulation and/or device used, the patient to be treated, and the like.Routes of administration useful in the disclosed methods include but arenot limited to oral and parenteral routes, such as intravenous (iv),intraperitoneal (ip), rectal, topical, ophthalmic, nasal, andtransdermal. Formulations for these dosage forms are described herein.

An effective amount of a subject compound may depend, at least, on theparticular method of use, the subject being treated, the severity of theaffliction, and the manner of administration of the therapeuticcomposition. A “therapeutically effective amount” of a composition is aquantity of a specified compound sufficient to achieve a desired effectin a subject (e.g., patient) being treated. For example, this may be theamount of a subject compound necessary to prevent, inhibit, reduce orrelieve a disease or disorder that is mediated through the activity of aPKC activity in a subject. Ideally, a therapeutically effective amountof a compound is an amount sufficient to prevent, inhibit, reduce orrelieve a disease or disorder that is mediated through the activity of aPKC activity in a subject without causing a substantial cytotoxic effecton host cells.

Therapeutically effective doses of a subject compound or pharmaceuticalcomposition can be determined by one of skill in the art, with a goal ofachieving local (e.g., tissue) concentrations that are at least as highas the IC₅₀ of an applicable compound disclosed herein.

An example of a dosage range is from 0.1 to 200 mg/kg body weight orallyin single or divided doses. In some embodiments, a dosage range is from1.0 to 100 mg/kg body weight orally in single or divided doses,including from 1.0 to 50 mg/kg body weight, from 1.0 to 25 mg/kg bodyweight, from 1.0 to 10 mg/kg body weight (assuming an average bodyweight of approximately 70 kg; values may be adjusted accordingly forpersons weighing more or less than average). For oral administration,the compositions are, for example, provided in the form of a tabletcontaining from about 10 to about 1000 mg of the active ingredient, suchas 25 to 750 mg, or 50 to 500 mg, for example 75 mg, 100 mg, 200 mg, 250mg, 400 mg, 500 mg, 600 mg, 750 mg, or 1000 mg of the active ingredientfor the symptomatic adjustment of the dosage to the subject beingtreated. In certain embodiments of an oral dosage regimen, a tabletcontaining from 500 mg to 1000 mg active ingredient is administered once(e.g., a loading dose) followed by administration of ½ (i.e., half)dosage tablets (e.g., from 250 to 500 mg) each 6 to 24 hours for 3 daysor more.

The specific dose level and frequency of dosage for any particularsubject may be varied and may depend upon a variety of factors,including the activity of the subject compound, the metabolic stabilityand length of action of that compound, the age, body weight, generalhealth, sex and diet of the subject, mode and time of administration,rate of excretion, drug combination, and severity of the condition ofthe host undergoing therapy.

Embodiments of the present disclosure also include combinations of oneor more disclosed compounds with one or more other agents or therapiesuseful in the treatment of a disease or disorder. In certain instances,the disease or disorder is mediated through the activity of a PKCactivity in a subject. In certain instances, the disease or disorder iscell proliferative disorder. For example, one or more disclosedcompounds may be administered in combination with therapeuticallyeffective doses of other medicinal and pharmaceutical agents, or incombination other non-medicinal therapies, such as hormone or radiationtherapy. The term “administration in combination with” refers to bothconcurrent and sequential administration of the active agents.

Protein Kinase C

Protein Kinase C (PKC)

PKC is a family of enzymes that function as serine/threonine kinases.The isoenzymes of PKC differ in their tissue distribution, enzymaticselectivity, requirement for Ca²⁺, and regulation. PKCs play animportant role in cell-cell signaling, gene expression and in thecontrol of cell differentiation and growth.

The subject compound can be a selective inhibitor of PKC, e.g. aninhibitor selective for PKC over one or more other protein kinases, e.g.over one or more tyrosine kinases, for instance, over one or morenon-receptor or receptor tyrosine kinases, e.g. over one or more of PKA,PKB, Abl Met, Src, Ins-R, Flt-3, JAK-2, KDR and/or Ret proteins. Theselective PKC inhibitors may optionally be selective over one or moreserine/threonine kinases, e.g. one or more serine/threonine kinaseswhich do not belong to the CDK family. The subject compounds can exhibita selectivity of at least 10 fold, or 20 fold, or 100 fold for the PKCover one or more other protein kinases, e.g. over one or more tyrosinekinases, e.g. over Flt-3, JAK-2, KDR and/or Ret proteins, or over one ormore serine/threonine kinases which do not belong to the CDK family.

The selectivity of a selective inhibitor of PKC over other proteinkinases may be calculated as the ratio of the IC₅₀ measured for PKC inan assay described herein over the IC₅₀ determined for another kinase.In a certain instance, there is provided a PKC inhibitor for which theratio of the IC₅₀ value as determined in an Allogeneic Mixed LymphocyteReaction (MLR) assay to the IC₅₀ value as determined in a Bone MarrowProliferation (BM) assay is higher than 5, 10, 20, or 30. MLR and BMassays can be done according to known methods, e.g. mouse or human MLRand BM assays, such as disclosed herein.

The disclosure provides an inhibitor of PKC, which can be anisozyme-selective PKC inhibitor, wherein the subject compound possessesselectivity for the isoforms θ and α of PKC over one or more of theother PKC isoforms. In a certain instance, the subject compoundpossesses selectivity for the isoform θ of PKC over one or more of theother PKC isoforms. In a certain instance, the subject compoundpossesses selectivity for the isoform α of PKC over one or more of theother PKC isoforms. In one embodiment, the disclosed compounds exhibitselectivity for PKC θ and PKC α over at least one PKC isoform.

A subject compound can show a selectivity of at least 10 fold, or 20fold, or 100 fold for the isoforms θ or α of PKC over one or more of theother PKC isoforms. Selectivity for the isoforms θ or α of PKC over oneor more of the other PKC isoforms can be measured by comparing the IC₅₀of the subject compound for the isoforms θ or α of PKC to the IC₅₀ ofthe subject compound for the other PKC isoforms. In certain instances,the selectivity can be determined by calculating the ratio of IC₅₀ ofthe subject compound for the other isoforms of PKC to the IC₅₀ of thesubject compound for θ or α isoforms of PKC. In certain examples subjectcompounds exhibit a selectivity for PKC θ, α or both over another PKCisoform of at least about 2-fold, such as from about 3-fold to about300-fold, from about 10-fold to about 100-fold or from about 5-fold to50-fold. IC₅₀ values are obtained, for example, according to PKC assaysdescribed herein. The subject compounds can show an IC₅₀ value for theisoforms θ or α of PKC of 1 μM or less, such as less than about 300 nM,such as from about 1 nM to about 250 nM, less than 100 nM or even lessthan 10 nM in the assays disclosed herein.

The subject compounds can show a selectivity of the isoforms θ or μ ofPKC over other isoforms of PKC, as well as a selectivity over one ormore of the other protein kinases, e.g. over one or more tyrosinekinases, or over one or more serine/threonine kinases which do notbelong to the CDK-family, e.g. over one or more of PKA, PKB, Abl, Met,Src, Ins-it, Flt-3, JAK-2, KDR and Ret proteins, e.g. over one or moreof Flt-3, JAK-2, KDR and Ret proteins.

Certain isozymes of PKC have been implicated in the mechanisms ofvarious disease states, including, but not necessarily limited to, thefollowing: cancer (PKC α, βI, βII, and δ); cardiac hypertrophy and heartfailure (PKC βI and PKC βII) nociception (PKC γ and ϵ); ischemiaincluding myocardial infarction (PKC ϵ and δ); immune response,particularly T-cell mediated (PKC θ and α); and fibroblast growth andmemory (PKC δ and ζ). The role of PKC ϵ is also implicated in painperception. PKC inhibitors can also be used for treating an oculardisease or disorder involving inflammatory and/or neovascular events.

The subject compounds can be used in the treatment of mammalian(especially human) disease states characterized by aberrant, elevatedactivity of a PKC isozyme in a tissue as compared to non-disease tissueof the same origin. PKC isozymes and disease states and/or biologicalfunctions amenable to therapy by inhibition of activity of the PKCisozyme include, but are not necessarily limited to: PKC α(hyperproliferative cellular diseases, such as cancer); PKC βI and PKCβII (cardiac hypertrophy and heart failure); PKC γ (pain management);PKC δ (ischemia, hypoxia (e.g., such as in myocardial infarction and instroke); apoptosis induced by UV irradiation; and aberrant fibroblastgrowth (e.g., as may occur in wound healing)); PKC ϵ (pain management,myocardial dysfunction); PKC θ (immune system diseases, particularlythose involving T-cell mediated responses); and PKC ζ (memory andfibroblast growth).

PKC Theta

PKC θ is expressed predominantly in lymphoid tissue and skeletal muscle.PKC θ is selectively expressed in T-cells and plays a role in matureT-cell activation. It has been shown that PKC θ is involved in T-cellreceptor (TCR)-mediated T-cell activation but inessential duringTCR-dependent thymocyte development. PKC θ, but not other PKC isoforms,translocates to the site of cell contact between antigen-specificT-cells and antigen presenting cells (APC), where it localizes with theTCR in the central core of the T-cell activation. PKC θ, but not the α,ϵ, or ζ isoenzymes, can selectively activate a FasL promoter-reportergene and upregulate the mRNA or cell surface expression of endogenousFasL. On the other hand, PKC θ and ϵ can promote T-cell survival byprotecting the cells from Fas-induced apoptosis, and this protectiveeffect was mediated by promoting p90Rsk-dependent phosphorylation ofBCL-2 family member BAD. Thus, PKC θ appears to play a dual regulatoryrole in T-cell apoptosis.

PKC θ inhibitors can find use in the treatment or prevention ofdisorders or diseases mediated by T lymphocytes, for example, autoimmunedisease such as rheumatoid arthritis, psoriasis and lupus erythematosus,and inflammatory disease such as asthma and inflammatory bowel diseases.

PKC θ is a drug target for immunosuppression in transplantation andautoimmune diseases (Isakov et al. (2002) Annual Review of Immunology,20, 761-794). PCT Publication WO2004/043386 identifies PKC θ as a targetfor treatment of transplant rejection and multiple sclerosis. PKC θ alsoplays a role in inflammatory bowel disease (The Journal of Pharmacologyand Experimental Therapeutics (2005), 313 (3), 962-982), asthma (WO2005062918), and lupus (Current Drug Targets: Inflammation & Allergy(2005), 4 (3), 295-298).

In addition, PKC θ is highly expressed in gastrointestinal stromaltumors (Blay, P. et al. (2004) Clinical Cancer Research, 10, 12, Pt. 1),it has been suggested that PKC θ is a molecular target for treatment ofgastrointestinal cancer (Wiedmann, M. et al. (2005) Current Cancer DrugTargets 5(3), 171).

Experiments induced in PKC θ knock-out mice led to the conclusion thatPKC θ inactivation prevented fat-induced defects in insulin signallingand glucose transport in skeletal muscle (Kim J. et al, 2004, The J. ofClinical Investigation 114 (6), 823). This data indicates PKC θ is atherapeutic target for the treatment of type 2 diabetes, and hence PKC θinhibitors can be useful for treating such disease.

Therapeutic Applications

The subject compounds are useful for treating a disease or disorder thatis mediated through, or exacerbated by, the activity of a PKC in asubject in need of treatment. Also, the compounds are useful fortreating a disease or disorder that is associated with aberrant orotherwise undesirable T cell activation in a subject.

Accordingly, the present disclosure provides methods of treating aninflammatory disease in a subject by administering an effective amountof a subject compound, including a salt or solvate or stereoisomerthereof, so as to treat inflammation. Inflammatory diseases contemplatedfor therapy include acute and chronic inflammation mediated orexacerbated by PKC activity.

The present disclosure also provides methods of treating an autoimmunedisease in a subject by administering to the subject an effective amountof a subject compound, including a salt or solvate or stereoisomerthereof, so as to treat the autoimmune disease.

The present disclosure also provides methods of treating an oculardisease or disorder involving inflammatory and/or neovascular events byadministration of a subject compound, including a salt or solvate orstereoisomer thereof, in an effective amount.

Diseases or conditions of interest for treatment according to thepresent disclosure include, but are not limited to, atherosclerosis,vascular occlusion due to vascular injury such as angioplasty,restenosis, obesity, syndrome X, impaired glucose tolerance, polycysticovary syndrome, hypertension, heart failure, chronic obstructivepulmonary disease, CNS diseases such as Alzheimer disease or amyotrophiclateral sclerosis, cancer, infectious diseases such as: AIDS, septicshock or adult respiratory distress syndrome, ischemia/reperfusioninjury, e.g., myocardial infarction, stroke, gut ischemia, renal failureor hemorrhage shock, and traumatic shock, e.g., traumatic brain injury.

Further diseases or conditions of interest for treatment according tothe present disclosure include, but are not limited to, T-cell mediatedacute or chronic inflammatory diseases or disorders or autoimmunediseases, rheumatoid arthritis, osteoarthritis, systemic lupuserythematosus, Hashimoto's thyroiditis, multiple sclerosis, myastheniagravis, diabetes type I or II and the disorders associated therewith,transplant rejection, graft versus host disease, respiratory diseases,asthma, inflammatory lung injury, inflammatory liver injury,inflammatory glomerular injury, cutaneous manifestations ofimmunologically-mediated disorders or illnesses, inflammatory andhyperproliferative skin diseases (such as psoriasis, atopic dermatitis,allergic contact dermatitis, irritant contact dermatitis and furthereczematous dermatitises, seborrhoeic dermatitis), inflammatory eyediseases (such as Sjoegren's syndrome, keratoconjunctivitis, uveitis)inflammatory bowel disease, Crohn's disease or ulcerative colitis,Guillain-Barre syndrome, and allergies.

The subject compounds can also be used for preventing or treating ordelaying ocular diseases and disorders involving inflammation and/orneovascularization. Ocular diseases or disorders involving inflammatoryand/or neovascular events include, but are not limited to, maculardegeneration (AMD), diabetic ocular diseases or disorders, uveitis,optic neuritis, ocular edema, ocular angiogenesis, ischemic retinopathy,anterior ischemic optic neuropathy, optic neuropathy and neuritis,macular edema, cystoid macular edema (CME), retinal disease or disorder,such as retinal detachment, retinitis pigmentosa (RP), Stargart'sdisease, Best's vitelliform retinal degeneration, Leber's congenitalamaurosis and other hereditary retinal degenerations, Sorsby's fundusdystrophy, pathologic myopia, retinopathy of prematurity (ROP), Leber'shereditary optic neuropathy, corneal transplantation or refractivecorneal surgery, keratoconjunctivitis, or dry eye.

Generally, cell proliferative disorders treatable with the subjectcompound disclosed herein relate to any disorder characterized byaberrant cell proliferation. These include various tumors and cancers,benign or malignant, metastatic or non-metastatic. Specific propertiesof cancers, such as tissue invasiveness or metastasis, can be targetedusing the methods described herein. Cell proliferative disorders includea variety of cancers, including, among others, breast cancer, ovariancancer, renal cancer, gastrointestinal cancer, kidney cancer, bladdercancer, pancreatic cancer, lung squamous carcinoma, and adenocarcinoma.

In some embodiments, the cell proliferative disorder treated is ahematopoietic neoplasm, which is aberrant growth of cells of thehematopoietic system. Hematopoietic malignancies can have its origins inpluripotent stem cells, multipotent progenitor cells, oligopotentcommitted progenitor cells, precursor cells, and terminallydifferentiated cells involved in hematopoiesis. Some hematologicalmalignancies are believed to arise from hematopoietic stem cells, whichhave the ability for self renewal. For instance, cells capable ofdeveloping specific subtypes of acute myeloid leukemia (AML) upontransplantation display the cell surface markers of hematopoietic stemcells, implicating hematopoietic stem cells as the source of leukemiccells. Blast cells that do not have a cell marker characteristic ofhematopoietic stem cells appear to be incapable of establishing tumorsupon transplantation (Blaire et al., 1997, Blood 89:3104-3112). The stemcell origin of certain hematological malignancies also finds support inthe observation that specific chromosomal abnormalities associated withparticular types of leukemia can be found in normal cells ofhematopoietic lineage as well as leukemic blast cells. For instance, thereciprocal translocation t(9q34; 22q11) associated with approximately95% of chronic myelogenous leukemia appears to be present in cells ofthe myeloid, erythroid, and lymphoid lineage, suggesting that thechromosomal aberration originates in hematopoietic stem cells. Asubgroup of cells in certain types of CML displays the cell markerphenotype of hematopoietic stem cells.

Although hematopoietic neoplasms often originate from stem cells,committed progenitor cells or more terminally differentiated cells of adevelopmental lineage can also be the source of some leukemias. Forexample, forced expression of the fusion protein Bcr/Abl (associatedwith chronic myelogenous leukemia) in common myeloid progenitor orgranulocyte/macrophage progenitor cells produces a leukemic-likecondition. Moreover, some chromosomal aberrations associated withsubtypes of leukemia are not found in the cell population with a markerphenotype of hematopoietic stem cells, but are found in a cellpopulation displaying markers of a more differentiated state of thehematopoietic pathway (Turhan et al., 1995, Blood 85:2154-2161). Thus,while committed progenitor cells and other differentiated cells may haveonly a limited potential for cell division, leukemic cells may haveacquired the ability to grow unregulated, in some instances mimickingthe self-renewal characteristics of hematopoietic stem cells (Passegueet al., Proc. Natl. Acad. Sci. USA, 2003, 100:11842-9).

In some embodiments, the hematopoietic neoplasm treated is a lymphoidneoplasm, where the abnormal cells are derived from and/or display thecharacteristic phenotype of cells of the lymphoid lineage. Lymphoidneoplasms can be subdivided into B-cell neoplasms, T and NK-cellneoplasms, and Hodgkin's lymphoma. B-cell neoplasms can be furthersubdivided into precursor B-cell neoplasm and mature/peripheral B-cellneoplasm. Exemplary B-cell neoplasms are precursor B-lymphoblasticleukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia) whileexemplary mature/peripheral B-cell neoplasms are B-cell chroniclymphocytic leukemia/small lymphocytic lymphoma, B-cell prolymphocyticleukemia, lymphoplasmacytic lymphoma, splenic marginal zone B-celllymphoma, hairy cell leukemia, plasma cell myeloma/plasmacytoma,extranodal marginal zone B-cell lymphoma of MALT type, nodal marginalzone B-cell lymphoma, follicular lymphoma, mantle-cell lymphoma, diffuselarge B-cell lymphoma, mediastinal large B-cell lymphoma, primaryeffusion lymphoma, and Burkitt's lymphoma/Burkitt cell leukemia. T-celland Nk-cell neoplasms are further subdivided into precursor T-cellneoplasm and mature (peripheral) T-cell neoplasms. Exemplary precursorT-cell neoplasm is precursor T-lymphoblastic lymphoma/leukemia(precursor T-cell acute lymphoblastic leukemia) while exemplary mature(peripheral) T-cell neoplasms are T-cell prolymphocytic leukemia T-cellgranular lymphocytic leukemia, aggressive NK-cell leukemia, adult T-celllymphoma/leukemia (HTLV-1), extranodal NK/T-cell lymphoma, nasal type,enteropathy-type T-cell lymphoma, hepatosplenic gamma-delta T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, Mycosisfungoides/Sezary syndrome, Anaplastic large-cell lymphoma, T/null cell,primary cutaneous type, Peripheral T-cell lymphoma, not otherwisecharacterized, Angioimmunoblastic T-cell lymphoma, Anaplastic large-celllymphoma, T/null cell, primary systemic type. The third member oflymphoid neoplasms is Hodgkin's lymphoma, also referred to as Hodgkin'sdisease. Exemplary diagnosis of this class that can be treated with thecompounds include, among others, nodular lymphocyte-predominantHodgkin's lymphoma, and various classical forms of Hodgkin's disease,exemplary members of which are Nodular sclerosis Hodgkin's lymphoma(grades 1 and 2), Lymphocyte-rich classical Hodgkin's lymphoma, Mixedcellularity Hodgkin's lymphoma, and Lymphocyte depletion Hodgkin'slymphoma.

In some embodiments, the hematopoietic neoplasm treated is a myeloidneoplasm. This group comprises a large class of cell proliferativedisorders involving or displaying the characteristic phenotype of thecells of the myeloid lineage. Myeloid neoplasms can be subdivided intomyeloproliferative diseases, myelodysplastic/myeloproliferativediseases, myelodysplastic syndromes, and acute myeloid leukemias.Exemplary myeloproliferative diseases are chronic myelogenous leukemia(e.g., Philadelphia chromosome positive (t(9; 22)(qq34; q11)), chronicneutrophilic leukemia, chronic eosinophilic leukemialhypereosinophilicsyndrome, chronic idiopathic myelofibrosis, polycythemia vera, andessential thrombocythemia. Exemplary myelodysplastic/myeloproliferativediseases are chronic myelomonocytic leukemia, atypical chronicmyelogenous leukemia, and juvenile myelomonocytic leukemia. Exemplarymyelodysplastic syndromes are refractory anemia, with ringedsideroblasts and without ringed sideroblasts, refractory cytopenia(myelodysplastic syndrome) with multilineage dysplasia, refractoryanemia (myelodysplastic syndrome) with excess blasts, 5q-syndrome, andmyelodysplastic syndrome with t(9; 12)(q22; p12) (TEL-Syk fusion; see,e.g., Kuno et al., 2001, Blood 97:1050).

In some embodiments, the composition can be used to treat acute myeloidleukemias (AML), which represent a large class of myeloid neoplasmshaving its own subdivision of disorders. These subdivisions include,among others, AMLs with recurrent cytogenetic translocations, AML withmultilineage dysplasia, and other AML not otherwise categorized.Exemplary AMLs with recurrent cytogenetic translocations include, amongothers, AML with t(8; 21)(q22; q22), AML1(CBF-alpha)/ETO, Acutepromyelocytic leukemia (AML with t(15; 17)(q22; q11-12) and variants,PML/RAR-alpha), AML with abnormal bone marrow eosinophils(inv(16)(p13q22) or t(16; 16)(p13; q11), CBFb/MYH11X), and AML with11q23 (MLL) abnormalities. Exemplary AML with multilineage dysplasia arethose that are associated with or without prior myelodysplasticsyndrome. Other acute myeloid leukemias not classified within anydefinable group include, AML minimally differentiated, AML withoutmaturation, AML with maturation, Acute myelomonocytic leukemia, Acutemonocytic leukemia, Acute erythroid leukemia, Acute megakaryocyticleukemia, Acute basophilic leukemia, and Acute panmyelosis withmyelofibrosis.

In other aspects, cell proliferative disorders comprise virally mediatedtumors. These can arise from infection of cells by an oncogenic virusthat has the capability of transforming a normal cell into a tumor cell.Because rates of viral infection far exceed the number of actualincidence of cell transformation, viral mediated transformationgenerally act together with other cellular factors to generate atransformed tumor cell. Thus, a virally mediated tumor does not requirethe virus to be the sole causative agent of the cell proliferativedisorder, but rather that the viral infection or persistent presence ofvirus is associated with the generation of the tumor. Generally, tumorswhere the causative agent is a virus typically has continual expressionof a limited number of viral genes and that viral these oncogenes,expressed as part of the viral infection or through persistence of thevirus, disrupts the normal cellular gene expression and signaltransduction pathways. Without being bound by theory, viral oncogenesinvolved in cell transformation appear to disrupt four main cellularprocesses: cell surface receptors that interact with growth factors andextracellular matrix, transmembrane signaling networks, cytosolicelements such as soluble proteins and second messengers, and nuclearproteins including DNA binding proteins and factors which functiondirectly and indirectly in gene regulation and replication.

Characterization of Functional Properties

The following are examples of assays useful in characterizing activitiesof a compound of the present disclosure.

A. In Vitro

1. Protein Kinase C Assay

The inhibition of PKC activity is measured by monitoring the productionof phosphorylated peptide by fluorescence polarization at differentconcentrations of the inhibitor. Reactions are carried out in 96-wellplate format with a total volume of 20 μL containing 20 mM HEPES, pH7.4, 5 mM MgCl₂, 0.2 mM CaCl₂, 1 mM DTT, 0.02% Brij-35, 0.1 mg/mlphosphatidylserine, 0.02 mg/ml dioleoyl-sn-glycerol and 5 μM each of ATPand the peptide substrate. Compounds are first diluted serially in DMSOand then transferred to a solution containing the above concentrationsof HEPES, MgCl₂, CaCl₂, DTT, and Brij-35 to yield 5× compound solutionsin 2% DMSO, which is then added to the reaction solution. Reactions areinitiated by the addition of PKC at a typical concentration as describedin the table below, and then allowed to incubate at room temperature for20 minutes. At the end of this time, a combination of quench (EDTA) anddetection (peptide tracer and antibody) reagents is added using theprotocol of Invitrogen P2748 (Carlsbad, Calif.), a Protein Kinase CFluorescence polarization Assay Kit. After a 30 minute period ofincubation, the amount of phosphorylated peptide generated is measuredby fluorescence polarization (Ex=485 nm, Em=535 nm) using a TecanPolarian instrument (Switzerland).

TABLE 2 enzyme Peptide concen- substrate SEQ ID Enzyme source trationPKC RFARKGSLR Seq ID  Upstate 40 theta QKNV No. 1 Biotechnologies, ng/mlTemecula, CA, cat. #14-444 PKC RFARKGSLR Seq ID  Upstate 50 epsilon QKNVNo. 1 Biotechnologies, ng/ml Temecula, CA,  cat. #14-518

2. IL-2 ELISA, Human Primary T Cell, Anti-CD3+CD28+ Assays

Human Primary T Cell Isolation and Culture:

Human primary T cells were prepared as follows. Fresh PBMC's from AllCells (Cat # PB002) were re-suspended in RPMI (RPMI-1640 withL-Glutamine; Mediatech, Inc., Herndon Va., cat. #10-040-CM) with 10% FBSand seeded into flasks and incubated at 37° C. for 2 hours to allow themonocytes to adhere. The non-adherent cells were then centrifuged andre-suspended in RPMI medium containing 40 U/ml IL2 and seeded into aflask pre-coated with 1 μg/ml aCD3 and 5 ug/ml aCD28 (Anti-Human CD3, BDPharmingen Catalog #555336, Anti-Human CD28, Beckman Coulter Catalog#IM1376). The cells were stimulated for 3-4 days, then transferred to afresh flask and maintained in RPMI (RPMI-1640 with L-Glutamine;Mediatech, Inc., Herndon Va., cat. #10-040-CM) with 10% FBS and 40 U/mlIL-2.

Primary T Cell Stimulation and IL2 ELISA:

Human primary T cells (100,000 cells per well) were pre-incubated withor without test compound in RPMI-1640 with L-Glutamine and 10% FBS for 1hour at 37° C. Cells were then stimulated by transferring them toround-bottom 96-well plates pre-coated with 1 μg/ml aCD3 and 5 μg/mlaCD28. For counter assay, cells were instead stimulated by adding 8×stock solutions of PMA and ionomycin in RPMI-1640 with L-Glutamine and10% FBS (for final concentrations of 0.5 ng/ml PMA and 0.1 μM ionomycin,both from Calbiochem). Cells were incubated at 37° C. for 24 hoursbefore 100 μL supernatants were harvested for quantification of IL-2 byELISA using Human IL-2 Duoset ELISA Kit from R and D Systems, Cat. #DY202E.

3. Protein Kinase C Assay

The subject compounds can be tested for activity on different PKCisoforms according to the following method. Assay is performed in awhite with clear bottom 384-well microtiterplate with non-bindingsurface. The reaction mixture (25 μl) contains 1.5 μM of atridecapeptide acceptor substrate that mimics the pseudo substratesequence of PKC α with the Ala→Ser replacement, 10 μM ³³P-ATP, 10 mMMg(NO₃)₂, 0.2 mM CaCl₂, PKG at a protein concentration varying from 25to 400 ng/ml (depending on the isotype used), lipid vesicles (containing30 mol % phosphatidylserine, 5 mol % DAG and 65 mol %phosphatidylcholine) at a final lipid concentration of 0.5 mM, in 20 mMTris-HCl buffer pH 7.4+0.1% BSA. Incubation is performed for 60 minutesat room temperature. Reaction is stopped by adding 50 μl of stop mix(100 mM EDTA, 200 μM ATP, 0.1% Triton X-100, 0.375 mg/wellstreptavidin-coated SPA beads in phosphate buffered saline w/o Ca, Mg.After 10 minutes incubation at room temperature, the suspension is spundown for 10 minutes at 300 g. Incorporated radioactivity is measured ina Trilux counter for 1 minute. IC₅₀ measurement is performed on aroutine basis by incubating a serial dilution of inhibitor atconcentrations ranging between 1-1000 μM. IC₅₀ values are calculatedfrom the graph by curve fitting with XL Fit® software.

4. Protein Kinase C α Assay

Human recombinant PKC α is obtained from Oxford Biomedical Research andis used under the assay conditions as described under Section A.1 above.

5. Protein Kinase C β1 Assay

Human recombinant PKC β1 is obtained from Oxford Biomedical Research andis used under the assay conditions as described under Section A.1 above.

6. Protein Kinase C δ Assay

Human recombinant PKC δ is obtained from Oxford Biomedical Research andis used under the assay conditions as described under Section A.1 above.

7. Protein Kinase C ϵ Assay

Human recombinant PKC ϵ is obtained from Oxford Biomedical Research andis used under the assay conditions as described under Section A.1 above.

8. Protein Kinase C η Assay

Human recombinant PKC η is obtained from PanVera and is used under theassay conditions as described under Section A.1 above.

9. Protein Kinase C θ Assay

Human recombinant PKC θ is used under the assay conditions as describedabove.

10. CD28 Costimulation Assay

The assay is performed with Jurkat cells transfected with a humaninterleukin-2 promoter/reporter gene construct as described by Baumann Get al. in Transplant. Proc. 1992; 24:43-8, the β-galactosidase reportergene being replaced by the luciferase gene (de Wet J., et al., Mol.Cell. Biol. 1987, 7(2), 725-737). Cells are stimulated by solidphase-coupled antibodies or phorbol myristate acetate (PMA) and the Ca⁺⁺ionophore ionomycin as follows. For antibody-mediated stimulationMicrolite TM1 microtiter plates (Dynatech) are coated with 3 μg/ml goatanti-mouse IgG Fc antibodies (Jackson) in 55 μl phosphate-bufferedsaline (PBS) per well for three hours at room temperature. Plates areblocked after removing the antibodies by incubation with 2% bovine serumalbumin (BSA) in PBS (300 μl per well) for 2 hours at room temperature.After washing three times with 300 μl PBS per well, 10 ng/ml anti-T cellreceptor antibodies (WT31, Becton & Dickinson) and 300 ng/ml anti-CD28antibodies (15E8) in 50 μl 2% BSA/PBS are added as stimulatingantibodies and incubated overnight at 4° C. Finally the plates arewashed three times with 300 μl PBS per well. Seven three-fold serialdilutions of test compounds in duplicates in assay medium (RPMI 1640/10%fetal calf serum (FCS) containing 50 μM 2-mercaptoethanol, 100 units/mlpenicillin and 100 μg/ml streptomycin) are prepared in separate plates,mixed with transfected Jurkat cells (clone K22 290_H23) and incubatedfor 30 minutes at 37° C. in 5% CO₂ 100 μl of this mixture containing1×10⁵ cells are then transferred to the antibody-coated assay plates. Inparallel 100 μl are incubated with 40 ng/ml PMA and 2 μM ionomycin.After incubation for 5.5 hours at 37° C. in 5% CO₂, the level ofluciferase is determined by bioluminescence measurement. The plates arecentrifuged for 10 minutes at 500 g and the supernatant is removed byflicking. Lysis buffer containing 25 mM Tris-phosphate, pH 7.8, 2 mMDTT, 2 mM 1,2-diaminocyclohexane-N,N,N′,N-tetraacetic acid, 10% (v/v)glycerol and 1% (v/v) Triton X-100 is added (20 μl per well). The platesare incubated at room temperature for 10 minutes under constant shaking.Luciferase activity is assessed with a bioluminescence reader(Labsystem, Helsinki, Finland) after automatic addition of 50 μl perwell luciferase reaction buffer containing 20 mM Tricine, 1.07 mM(MgCO₃)₄Mg(OH)₂×5H₂O, 2.67 mM MgSO₄, 0.1 mM EDTA, 33.3 mM DTT, 270 μMcoenzyme A, 470 μM luciferin (Chemie Brunschwig AG), 530 μM ATP, pH 7.8.Lag time is 0.5 seconds, total measuring time is 1 or 2 seconds. Lowcontrol values are light units from anti-T cell receptor- orPMA-stimulated cells, high controls are from anti-T cellreceptor/anti-CD28- or PMA/ionomycin-stimulated cells without any testsample. Low controls are subtracted from all values. The inhibitionobtained in the presence of a test compound is calculated as percentinhibition of the high control. The concentration of test compoundsresulting in 50% inhibition (IC₅₀) is determined from the dose-responsecurves.

11. Bone Marrow Proliferation (BM) Assay

Bone marrow cells from CBA mice (2.5×104 cells per well in flat bottomtissue culture microtiter plates) are incubated in 100 μl RPMI mediumcontaining 10% FCS, 100 U/ml penicillin, 100 μg/ml streptomycin (GibcoBRL, Basel, Switzerland), 50 UM 2-mercaptoethanol (Fluke, Buchs,Switzerland), WEHI-3 conditioned medium (7.5% v/v) and L929 conditionedmedium (3% v/v) as a source of growth factors and serially dilutedcompounds. Seven three-fold dilution steps in duplicates per testcompound are performed. After four days of incubation 1 μCi³H-thymidineis added. Cells are harvested after an additional five-hour incubationperiod, and incorporated ³H-thymidine is determined according tostandard procedures. Conditioned media are prepared as follows. WEHI-3cells 1 (ATCC TIB68) and L929 cells (ATCC CCL 1) are grown in RPMImedium until confluence for 4 days and one week, respectively. Cells areharvested, resuspended in the same culture flasks in medium C containing1% FCS (Schreier and Tees 1981) for WEHI-3 cells and RPMI medium forL929 cells and incubated for 2 days (WEHI-3) or one week (L929). Thesupernatant is collected, filtered through 0.2 μm and stored in aliquotsat −80° C. Cultures without test compounds and without WEHI-3 and L929supernatants are used as low control values. Low control values aresubtracted from all values. High controls without any sample are takenas 100% proliferation. Percent inhibition by the samples is calculatedand the concentrations required for 50% inhibition (IC₅₀ values) aredetermined.

12. Allogeneic Mixed Lymphocyte Reaction (MLR)

The two-way MLR is performed according to standard procedures (J.Immunol. Methods, 1973, 2, 279 and Meo T. et al., Immunological Methods,New York, Academic Press, 1979, 227-39). Briefly, spleen cells from CBAand BALB/c mice (1.6×10⁵ cells from each strain per well in flat bottomtissue culture microtiter plates, 3.2×10⁵ in total) are incubated inRPMI medium containing 10% FCS, 100 U/ml penicillin, 100 μg/mlstreptomycin (Gibco BRL, Basel, Switzerland), 50 μM 2-mercaptoethanol(Fluka, Buchs, Switzerland) and serially diluted compounds. Seventhree-fold dilution steps in duplicates per test compound are performed.After four days of incubation 1 μCi³H-thymidine is added. Cells areharvested after an additional five-hour incubation period, andincorporated ³H-thymidine is determined according to standardprocedures. Background values (low control) of the MLR are theproliferation of BALB/c cells alone. Low controls are subtracted fromall values. High controls without any sample are taken as 100%proliferation. Percent inhibition by the samples is calculated, and theconcentrations required for 50% inhibition (IC₅₀ values) are determined.

B. In Vivo

1. Heart Transplantation Model

The strain combination used: Male Lewis (RT¹ haplotype) and BN (RT¹haplotype). The animals are anaesthetised using inhalationalisofluorane. Following heparinisation of the donor rat through theabdominal inferior vena cava with simultaneous exsanguination via theaorta, the chest is opened and the heart rapidly cooled. The aorta isligated and divided distal to the first branch and the brachiocephalictrunk is divided at the first bifurcation. The left pulmonary artery isligated and divided and the right side divided but left open. All othervessels are dissected free, ligated and divided and the donor heart isremoved into iced saline.

The recipient is prepared by dissection and cross-clamping of theinfra-renal abdominal aorta and vena cava. The graft is implanted withend-to-side anastomoses, using 1010 monofilament suture, between thedonor brachiocephalic trunk and the recipient aorta and the donor rightpulmonary artery to the recipient vena cava. The clamps are removed, thegraft tethered retroabdominally, the abdominal contents washed with warmsaline and the animal is closed and allowed to recover under a heatinglamp. Graft survival is monitored by daily palpation of the beatingdonor heart through the abdominal wall. Rejection is considered to becomplete when-heart beat stops. Graft survival is monitored in animalstreated with compounds.

2. Graft v. Host Model

Spleen cells (2×10⁷) from Wistar/F rats are injected subcutaneously intothe right hind footpad of (Wistar/F×Fischer 344)F₁ hybrid rats. The leftfootpad is left untreated. The animals are treated with the testcompounds on 4 consecutive days (0-3). The popliteal lymph nodes areremoved on day 7, and the weight differences between two correspondinglymph nodes are determined. The results are expressed as the inhibitionof lymph node enlargement (given in percent) comparing the lymph nodeweight differences in the experimental groups to the weight differencebetween the corresponding lymph nodes from a group of animals leftuntreated with a test compound. In certain instances the test compoundis a selective PKC inhibitor. For example, disclosed compounds that areparticularly useful for treating graft versus host disease and relateddisorders are selective PKC α and θ inhibitors.

3. Rat Collagen-Induced Arthritis Model

Rheumatoid arthritis (RA) is characterized by chronic joint inflammationeventually leading to irreversible cartilage destruction. IgG-containingIC are abundant in the synovial tissue of patients with RA. While it isstill debated what role these complexes play in the etiology andpathology of the disease, IC communicate with the hematopoetic cells viathe FcγR.

CIA is a widely accepted animal model of RA that results in chronicinflammatory synovitis characterized by pannus formation and jointdegradation. In this model, intradermal immunization with native type IIcollagen, emulsified with incomplete Freund's adjuvant, results in aninflammatory polyarthritis within 10 or 11 days and subsequent jointdestruction in 3 to 4 weeks.

4. Study Protocol

Syngeneic LOU rats are immunized with native type II collagen on Day 0,and efficacy of a test compound is evaluated in a prevention regimen anda treatment regimen. In the prevention protocol, either vehicle orvarious doses of a test compound are administered via oral gavagestarting on day of immunization (Day 0). In the treatment protocol,after clinical signs of arthritis develop on Day 10, treatment with atest compound is initiated (e.g., 300 mg/kg by oral gavage, qd) andcontinued until sacrifice on Day 28. In both protocols, clinical scoresare obtained daily, and body weights are measured twice weekly. At Day28, radiographic scores are obtained, and serum levels of collagen IIantibody are measured by ELISA.

5. Determination of Results

By 10 days after immunization, rats can develop clinical CIA, asdetermined by an increase in their arthritis scores. The mean arthriticscore gradually increases in the rats treated with vehicle alone afterDay 10, and by Day 28 the mean clinical score can reach about 6.75. Meanclinical scores in animals treated from the day of immunization (Day 0)with a test compound can be significantly reduced on Days 10-28 comparedwith vehicle controls. In the rats treated with a test compound atdisease onset, there can be a significantly lower arthritis scorebeginning around Day 16, and this difference can be observed until theend of the study on Day 28.

Blinded radiographic scores (scale 0-6) can be obtained on Day 28 of CIAand compared between the animals in the vehicle group, animals in theprevention group, and animals in the treatment group.

The groups administered with a test compound, either prophylactically(at immunization) or after disease onset can preclude the development oferosions and reduced soft tissue swelling. Similarly, the groupsadministered with a test compound can result in reduction of serumanti-collagen II antibody.

6. Mouse Experimental Autoimmune Encephalomyelitis

The in vivo efficacy of a test compound towards autoimmune diseases canbe demonstrated in a mouse model of experimental autoimmuneencephalomyelitis (EAE).

7. Model Description

EAE is a useful model for multiple sclerosis (MS), an autoimmune diseaseof the CNS that is caused by immune-cell infiltration of the CNS whitematter. Inflammation and subsequent destruction of myelin causeprogressive paralysis. Like the human disease, EAE is associated withperipheral activation of T cells autoreactive with myelin proteins, suchas myelin basic protein (MBP), proteolipid protein (PLP), or myelinoligodendrocyte protein (MOG). Activated neuroantigen-specific T cellspass the blood-brain barrier, leading to focal mononuclear cellinfiltration and demyelination. EAE can be induced in susceptible mousestrains by immunization with myelin-specific proteins in combinationwith adjuvant. In the SJL mouse model used in these studies, hind limband tail paralysis is apparent by Day 10 after immunization, the peak ofdisease severity can be observed between Days 10 and 14, and a cycle ofpartial spontaneous remission followed by relapse can be observed up toDay 35. The results can demonstrate the potential of the test compoundto suppress disease severity and prevent relapse of disease symptomsthat may be the result of FcγR-mediated cytokine release from immunecells.

8. Study Protocol

In the SJL murine model of EAE, each mouse is sensitized with PLP/CFA.(150 μg PLP139-151 with 200 μg CFA in 0.05 ml of homogenate on foursites of hind flank for a total of 0.2 ml emulsion is used to induceEAE). In a suppression protocol, either vehicle or various doses of atest compound are administered via oral gavage starting on the day ofimmunization (Day 0). In a treatment protocol, at onset of disease,animals are separated to achieve groups with a similar mean clinicalscore at onset and administered vehicle or various dose frequencies oftest compounds via oral gavage. In both protocols, clinical scores aremonitored daily, and body weights are measured twice weekly.

9. Determination of Results

By 10 days after PLP immunization, SJL mice can develop clinical EAE, asevidenced by an increase in their mean clinical scores. The paralyticscore can gradually increase in the animals treated with vehicle onlyfrom the day of immunization (Day 0), and by Day 14 the mean score canreach a peak of about 5.1. At disease peak (e.g., Day 14), the meanclinical score in animals treated with either daily or twice daily canbe significantly reduced. By Day 16, animals can exhibit a partialremission of mean clinical severity, which is a characteristic of theSJL model. The lower clinical scores in animals treated twice daily witha test compound can remain significant throughout the experiment untilthe animals are sacrificed on Day 30. These lower scores throughout thetreatment period are reflected in the significantly lower cumulativedisease index (CDI) and increase in cumulative weight index (CWI).

SJL mice treated with a test compound at disease onset (e.g., Day 11)can show a significant decrease in CDI. Further, there can be a decreasein the number of relapses in animals treated with a test compoundcompared with the number of relapses in animals treated with vehicle.

Research Applications

Since subject compounds can inhibit a PKC activity, such compounds arealso useful as research tools. The present disclosure also provides amethod for using subject compounds as a research tool for studying abiological system or sample, or for discovering new chemical compoundsthat can inhibit a PKC activity.

The disclosure provides for a method of studying a biological system orsample known to comprise PKC, the method comprising: (a) contacting thebiological sample with a compound of formula I-IV or a salt or solvateor stereoisomer thereof; and (b) determining the inhibiting effectscaused by the compound on the biological sample.

Any suitable biological sample having PKC can be employed in suchstudies which can be conducted either in vitro or in vivo.Representative biological samples suitable for such studies include, butare not limited to, cells, cellular extracts, plasma membranes, tissuesamples, isolated organs, mammals (such as mice, rats, guinea pigs,rabbits, dogs, pigs, humans, and so forth), and the like, with mammalsbeing of particular interest.

When used as a research tool, a biological sample comprising PKC istypically contacted with a PKC activity-inhibiting amount of a subjectcompound. After the biological sample is exposed to the compound, theeffects of inhibition of a PKC activity are determined usingconventional procedures and equipment, such as the assays disclosedherein. Exposure encompasses contacting the biological sample with thecompound or administering the compound to a subject. The determiningstep can involve measuring a response (a quantitative analysis) or caninvolve making an observation (a qualitative analysis). Measuring aresponse involves, for example, determining the effects of the compoundon the biological sample using conventional procedures and equipment,such as radioligand binding assays and measuring ligand-mediated changesin functional assays. The assay results can be used to determine theactivity level as well as the amount of compound necessary to achievethe desired result, that is, a PKC activity-inhibiting amount.

Additionally, subject compounds can be used as research tools forevaluating other chemical compounds, and thus are also useful inscreening assays to discover, for example, new compounds having a PKCinhibiting activity. In this manner, a subject compound can be used as astandard in an assay to allow comparison of the results obtained with atest compound and with the subject compounds to identify those testcompounds that have about equal or superior activity, if any. Forexample, IC₅₀ data for a test compound or a group of test compounds iscompared to the IC₅₀ data for a subject compound to identify those testcompounds that have the desired properties, for example, test compoundshaving an IC₅₀ about equal or superior to a subject compound, if any.

This aspect includes, as separate embodiments, both the generation ofcomparison data (using the appropriate assays) and the analysis of testdata to identify test compounds of interest. Thus, a test compound canbe evaluated in a biological assay, by a method comprising the steps of:(a) conducting a biological assay with a test compound to provide afirst assay value; (b) conducting the biological assay with a subjectcompound to provide a second assay value; wherein step (a) is conductedeither before, after or concurrently with step (b); and (c) comparingthe first assay value from step (a) with the second assay value fromstep (b). The assays that can be used for generation of comparison dataare disclosed herein, such as the PKC assays.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the embodiments, and are not intended to limit the scope ofwhat the inventors regard as their invention nor are they intended torepresent that the experiments below are all or the only experimentsperformed. Efforts have been made to ensure accuracy with respect tonumbers used (e.g. amounts, temperature, etc.) but some experimentalerrors and deviations should be accounted for. As will be understood, bythose of skill in the art of organic synthesis and medicinal chemistrythe specific conditions set forth below are exemplary and can be variedor adapted to other reagents and products in routine fashion. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Celsius, andpressure is at or near atmospheric. Standard abbreviations may be used.

As referred to in the Examples, HPLC and LCMS protocols are as follows:

Protocol-1:

HPLC: Waters 2690 Alliance

Diode array detector (210-400 nm)

Column: Phenomenex Gemini 4.6×100 mm, Sum, 110 Å

Column temperature 30° C.

Sample temperature 15° C.

Solvent A—0.05% Formic acid in Water

Solvent B—0.05% Formic acid in Acetonitrile

Flow rate—1.5 ml/min

Gradient:

Time A % B % 0 95 5 10 0 100 (curve = 6) 11.1 0 100 11.2 95 5 12.1 95 5

Protocol-2:

HPLC: Waters 2690 Alliance

Diode array detector (210-400 nm)

Column: Phenomenex Gemini 4.6×100 mm, Sum, 110 Å

Column temperature 30° C.

Sample temperature 15° C.

Solvent A—0.05% Formic acid in Water

Solvent B—0.05% Formic acid in Acetonitrile

Flow rate—1.5 ml/min

Gradient:

Time A % B % 0 95 5 10 0 100 (curve = 8) 11.1 0 100 11.2 95 5 12.1 95 5

Protocol-3:

HPLC: Waters 2695 Alliance

Diode array detector (210-400 nm)

Column: Phenomenex Gemini 4.6×100 mm, 5 um, 110 Å

Column temperature 30° C.

Sample temperature 15° C.

Solvent A—0.05% Formic acid in Water

Solvent B—0.05% Formic acid in Acetonitrile

Flow rate—1.5 ml/min

Gradient:

Time A % B % 0 95 5 10 0 100 (curve = 6) 11.1 0 100 11.2 95 5 12.1 95 5

Chiral HPLC methods:

Protocol-4:

HPLC: Waters 2695 Alliance

Diode array detector (210-400 nm)

Column: Chiralcel-OJ, 4.6×250 mm, with guard

Mobil phase (isocratic): 40% methanol, 40% ethanol, 19.9% Hexane, 0.1%triethylamine

Flow rate: 0.5 ml/min

Injection volume: 3 μL

Concentration: approx 5 mg/ml

Detection: UV at 254 nm

Run Time: 30 minutes

Protocol-5:

HPLC: Waters 2695 Alliance

Diode array detector (210-400 nm)

Column: Chiralcel-OJ, 4.6×250 mm, with guard

Mobil phase (isocratic): 89.9% Hexane, 5% methanol, 5% ethanol 0.1%triethylamine

Flow rate: 0.5 ml/min

Injection volume: 3 μL

Concentration: approx 5 mg/ml

Detection: UV at 254 nm

Run Time: 45 minutes

Example 1 General Scheme for the Synthesis of Lupinane PKC Inhibitors

General Procedure for the Synthesis of the Lupinane Mono-SNAr Product:

The lupinane amine •2HCl(1-[(1S,9aR)-octahydro-2H-quinolizin-1-yl]methanamine, CAS #:75532-84-2, commercially available from ChemBridge, San Diego) (1.0 eq)was combined with 2,4-dichloro-5-X-pyrimidine (X═H, F, Cl, Me, CF₃, CN,CONH₂, OMe, NMe₂) (1.0 eq) and NaHCO₃ (1.2 eq). A mixture of MeOH:H₂O(4/1) (concentration of the reaction mixture: ca. 0.1-0.5 M) was addedand the resulting suspension was stirred for 1 d at RT. After thecompletion of the reaction was confirmed by TLC and HPLC, silica gel wasadded to the reaction mixture and solvents were evaporated under reducedpressure. The resulting solid was loaded on a CombiFlash column andfurther purified by flash chromatography eluting with DCM/MeOH—NH₃ (2M)(gradient 0→10%).

General Procedure for the Installment of the N2 Substituent (2^(nd)S_(N)Ar):

The mono-S_(N)Ar product (50.0 mg, 1.0 eq) was dissolved in 4 ml ofisopropyl alcohol in a 2 dram vial. p-Toluenesulfonic acid monohydrate(1.2 eq) and the desired aniline (1.5 eq) were added and the vial wassealed. After heating over night at 80° C. using an anodized aluminumheating block the solvent was boiled off by removing the cap. Theproduct was isolated by preparative HPLC eluting with anacetonitrile/water gradient.

Synthesis of Right-Hand Side (RHS) Anilines:

Preparation of 5-amino-2-bromo-4-fluorobenzonitrile

3-amino-4-fluorobenzonitrile (9.82 g, 72.1 mmol) was dissolved inacetonitrile to give a pale yellow solution. NBS (13.5 g, 75.7 mmol) wasadded in portions; the reaction mixture turned brown-blackish butremained a solution. After the completion of the reaction was confirmedby TLC and HPLC, silica gel was added to the reaction mixture and thesolvent was evaporated under reduced pressure. The crude product wasleaded on a CombiFlash column (330 g) and the product was eluted withhexanes/ethyl acetate (0→15% gradient). The clean fractions werecombined to give 9.63 g (62%) of a yellowish off-white solid. Moreproduct was found in mixed fractions which were discarded. ¹H NMR (300MHz, dmso) δ 7.57 (d, J=10.9 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 5.85 (sbr, 2H); MS (ES) 213/215 (M−H).

Preparation of 5-amino-2-cyclopropyl-4-fluorobenzonitrile

The product from the above reaction(5-amino-2-bromo-4-fluorobenzonitrile) (4.0 g, 18.6 mmol), cyclo-propylboronic acid (3.19 g, 37.2 mmol), Pd(OAc)₂ (835 mg, 3.72 mmol),tricyclohexyl phosphine (1.04 g, 3.72 mmol), Cs₂CO₃ (36.3 g, 111.6 mmol)were combined in a pressure vessel. A mixture of toluene (110 ml) andH₂O (35 ml) was added. The ensuing yellow-orange suspension was degassedand flushed with nitrogen gas (3×). The pressure vessel was sealed andheated over night (ca. 12 h) at 110° C. After checking the reaction byTLC and HPLC, the precipitate/salts were filtered off, more H₂O wasadded and the mixture was extracted with ethyl acetate (3×). Thecombined organic phases were filtered through Na₂SO₄, silica gel wasadded and solvents were removed using a rotary evaporator. Furtherpurification by CombiFlash (120 g column) eluting with hexanes/ethylacetate (0→20% gradient) yielded 2.01 g (61%) of the desired product inform of a pale yellow, beige solid. ¹H NMR (300 MHz, cdcl₃) δ 6.98 (d,J=8.6 Hz, 1H), 6.58 (d, J=12.0 Hz, 1H), 3.81 (s br, 2H), 2.21-2.06 (m,1H), 1.11-0.99 (m, 2H), 0.69-0.59 (m, 2H); MS (ES) 177 (M+H).

Example 25-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-2-cyclopropylbenzonitrile(Compound 1)

Compound 1 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.22 (s, 1H), 8.12 (s, 1H), 7.84 (d, J=3.7 Hz,1H), 7.79 (d, J=8.7 Hz, 1H), 7.51 (s, 1H), 6.92 (d, J=8.8 Hz, 1H),3.64-3.44 (m, 2H), 3.41-3.21 (m, 4H), 2.71 (d, J=9.3 Hz, 2H), 2.48 (s,2H), 2.13-1.98 (m, 1H), 1.98-1.73 (m, 7H), 1.68 (d, J=13.4 Hz, 4H),1.59-1.33 (m, 4H), 1.33-1.08 (m, 3H), 1.01 (d, J=10.2 Hz, 2H), 0.70 (d,J=4.8 Hz, 2H); MS (ES) 421 (M+H).

Example 3:N2-(4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)phenyl)-5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine(Compound 2, formate salt)

Compound 2 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.87 (dd, J=12.6, 0.6 Hz, 1H), 8.10 (dd, J=9.3,4.1 Hz, 1H), 7.97 (d, J=4.1 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.13-7.00(m, 2H), 3.57-3.02 (m, 5H), 3.02-2.74 (m, 2H), 2.33-1.99 (m, 2H),1.90-1.08 (m, 20H), 0.76 (dd, J=18.3, 9.8 Hz, 2H), 0.72-0.53 (m, 2H); MS(ES) 482 (M+H).

Example 4:1-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one(Compound 3, formate salt)

Compound 3 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 8.16-8.09 (m, 1H), 8.04 (t, J=4.4 Hz, 2H), 7.84(d, J=7.6 Hz, 1H), 7.62 (d, J=7.5 Hz, 1H), 3.61 (s, 3H), 3.55-3.04 (m,3H), 3.02-2.73 (m, 2H), 2.55-2.40 (m, 2H), 2.31-1.86 (m, 4H), 1.82-1.10(m, 4H), 0.88 (t, J=8.0 Hz, 2H), 0.69 (dd, J=12.0, 4.8 Hz, 2H); MS (ES)512 (M+H).

Example 5:5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methyl-3-(1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine(Compound 4, formate salt)

Compound 4 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.94 (d, J=10.0 Hz, 2H), 9.25 (s, 1H), 8.80 (s,1H), 8.53 (s, 1H), 8.09 (t, J=3.6 Hz, 1H), 7.96-7.85 (m, 1H), 7.62 (d,J=10.6 Hz, 2H), 3.53-3.22 (m, 3H), 3.22-3.07 (m, 2H), 3.03-2.77 (m, 2H),2.31-2.08 (m, 6H), 2.07 (s, 3H), 1.86-1.10 (m, 5H); MS (ES) 438 (M+H).

Example 6:5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methoxy-3-(5-methyl-1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine(Compound 6, trifluoroacetate salt)

Compound 6 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.08-9.83 (m, 1H), 9.66 (s, 1H), 8.05 (t,J=3.9 Hz, 1H), 7.77 (dd, J=9.0, 2.5 Hz, 1H), 7.68 (dd, J=9.0, 2.6 Hz,1H), 7.31 (dd, J=9.1, 2.3 Hz, 1H), 3.77 (s, 3H), 3.56-3.04 (m, 3H),3.03-2.73 (m, 4H), 2.50-2.43 (m, 1H), 2.37 (s, 3H), 2.29-2.07 (m, 4H),1.89-1.10 (m, 7H); MS (ES) 468 (M+H).

Example 7:5-fluoro-N2-(2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine(Compound 7, trifluoroacetate salt)

Compound 7 was prepared as described in Example 1.

MS (ES) 456 (M+H).

Example 8:5-fluoro-N2-(4-fluoro-3-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine(Compound 8, trifluoroacetate salt)

Compound 8 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.38-10.13 (m, 1H), 9.92-9.34 (m, 1H),8.67-8.30 (m, 1H), 8.17-8.03 (m, 1H), 7.97-7.71 (m, 1H), 7.53 (dd,J=23.0, 13.4 Hz, 1H), 3.73-3.06 (m, 5H), 3.05-2.75 (m, 2H), 2.49 (s,3H), 2.36-2.02 (m, 2H), 1.91-1.06 (m, 9H); MS (ES) 456 (M+H).

Example 9:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-2-methylbenzonitrile(Compound 9, formate salt)

Compound 9 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.87 (s, 1H), 9.29 (s, 1H), 8.80 (d, J=11.1 Hz,1H), 8.10 (dd, J=10.3, 3.6 Hz, 1H), 7.69-7.57 (m, 1H), 7.44-7.33 (m,1H), 3.70-3.56 (m, 2H), 3.54-3.12 (m, 2H), 3.04-2.79 (m, 2H), 2.41 (d,J=4.5 Hz, 1H), 2.27 (s, 3H), 2.20-2.03 (m, 4H), 1.91-1.65 (m, 3H), 1.58(s, 2H), 1.50-1.20 (m, 2H); MS (ES) 395 (M+H).

Example 10:3-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)benzonitrile(Compound 10, formate salt)

Compound 10 was prepared as described in Example 1.

MS (ES) 381 (M+H).

Example 11:5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3,5-dimethoxyphenyl)pyrimidine-2,4-diamine(Compound 11, formate salt)

Compound 11 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.12 (d, J=19.2 Hz, 1H), 9.44-9.16 (m, 2H),8.28-8.01 (m, 1H), 6.76 (d, J=2.1 Hz, 1H), 6.63 (d, J=2.2 Hz, 1H),6.42-6.21 (m, 1H), 3.78-3.65 (m, 2H), 3.57-3.34 (m, 2H), 3.34-3.01 (m,2H), 3.05-2.74 (m, 1H), 2.39-1.98 (m, 3H), 2.00-1.62 (m, 4H), 1.64-1.16(m, 4H); MS (ES) 416 (M+H).

Example 12:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-2-cyclopropyl-4-fluorobenzonitrile(Compound 12, formate salt)

Compound 12 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 8.84 (s, 1H), 7.94 (t, J=3.4 Hz, 1H), 7.01 (d,J=12.2 Hz, 1H), 3.64-3.38 (m, 2H), 3.29 (d, J=6.9 Hz, 2H), 3.17 (d,J=6.3 Hz, 2H), 3.03-2.76 (m, 1H), 2.12 (s, 1H), 1.89-1.66 (m, 6H),1.65-1.48 (m, 4H), 1.50-1.30 (m, 2H), 1.09 (d, J=8.0 Hz, 2H), 0.91-0.74(m, 2H); MS (ES) 439 (M+H).

Example 13:5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-phenylpyrimidine-2,4-diamine(Compound 13, formate salt)

Compound 13 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.09 (d, J=14.5 Hz, 1H), 9.43-9.10 (m, 1H),8.16 (td, J=5.4, 1.7 Hz, 1H), 7.48-7.27 (m, 3H), 7.26-7.12 (m, 2H),3.70-3.08 (m, 2H), 3.03-2.71 (m, 2H), 2.54-2.42 (m, 2H), 2.17-1.98 (m,1H), 1.93-1.63 (m, 4H), 1.63-1.50 (m, 4H), 1.49-1.19 (m, 3H); MS (ES)356 (M+H).

Example 14:5-chloro-N2-(4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine(Compound 32, bis-formate salt)

Compound 32 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.85 (d, J=14.6 Hz, 1H), 9.00-8.67 (m, 1H),7.95 (d, J=8.9 Hz, 1H), 7.21-7.11 (m, 1H), 3.50-3.02 (m, 2H), 2.99-2.61(m, 4H), 2.12 (s, 1H), 1.96-1.25 (m, 6H), 1.22 (dd, J=6.2, 2.6 Hz, 6H),0.99-0.44 (m, 4H); MS (ES) 498 (M+H).

Example 15:5-chloro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methyl-3-(1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine(Compound 33, bis-formate salt)

Compound 33 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.86 (d, J=9.6 Hz, 1H), 8.06 (d, J=5.1 Hz, 1H),8.00-7.85 (m, 1H), 7.71 (dd, J=14.1, 5.9 Hz, 1H), 7.41 (d, J=8.5 Hz,1H), 3.70-3.53 (m, 2H), 3.53-3.06 (m, 4H), 3.04-2.74 (m, 1H), 2.30-2.13(m, 4H), 2.07 (s, 3H), 1.89-1.62 (m, 3H), 1.62-1.31 (m, 2H), 1.30-1.10(m, 2H); MS (ES) 454 (M+H).

Example 16:1-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-chloropyrimidin-2-ylamino)-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one(Compound 34, bis-formate salt)

Compound 34 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 8.80 (d, J=23.6 Hz, 1H), 7.91 (d, J=10.5 Hz,1H), 7.45-7.31 (m, 1H), 7.00 (dd, J=11.9, 7.8 Hz, 1H), 3.62 (s, 3H),3.56-3.04 (m, 3H), 3.02-2.72 (m, 3H), 2.23-1.98 (m, 1H), 1.94-1.44 (m,6H), 1.44-1.12 (m, 6H), 0.92-0.77 (m, 2H), 0.66 (dd, J=8.6, 4.3 Hz, 2H);MS (ES) 428 (M+H).

Example 17:5-chloro-N2-(4-fluoro-3-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine(Compound 35, bis-formate salt)

Compound 35 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 8.18-8.05 (m, 1H), 7.98 (d, J=7.3 Hz, 1H), 7.86(d, J=9.0 Hz, 1H), 7.40 (s, 1H), 3.53-3.07 (m, 4H), 2.95 (m, 2H), 2.26(m, 1H), 2.00-1.60 (m, 8H), 1.60-1.13 (m, 6H); MS (ES) 472 (M+H).

Example 18:5-chloro-N2-(2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine(Compound 36, bis-formate salt)

Compound 36 was prepared as described in Example 1.

MS (ES) 472 (M+H).

Example 19:5-chloro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methoxy-3-(5-methyl-1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine(Compound 37)

Compound 37 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.62-9.41 (m, 1H), 8.01 (d, J=3.5 Hz, 1H),7.96-7.83 (m, 1H), 7.77 (ddd, J=14.4, 9.1, 2.5 Hz, 1H), 7.70-7.54 (m,1H), 7.29 (dd, J=9.2, 3.5 Hz, 1H), 3.76 (s, 3H), 3.70-3.34 (m, 3H),3.36-3.04 (m, 2H), 3.03-2.69 (m, 2H), 2.37 (s, 3H), 2.19-2.03 (m, 2H),1.98-1.07 (m, 9H); MS (ES) 484 (M+H).

Example 20:5-chloro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine(Compound 38)

Compound 38 was prepared as described in Example 1.

MS (ES) 484 (M+H).

Example 21:3-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-chloropyrimidin-2-ylamino)benzonitrile(Compound 39)

Compound 39 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.51 (s, 1H), 8.20 (s, 1H), 8.00-7.92 (m, 1H),7.69 (s, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.30 (d, J=6.3 Hz, 1H), 3.59 (t,J=5.5 Hz, 1H), 3.30 (m, 2H), 2.74 (d, J=10.3 Hz, 2H), 2.48 (dd, J=3.1,1.8 Hz, 2H), 2.02-1.76 (m, 4H), 1.73-1.58 (m, 2H), 1.57-1.25 (m, 4H),1.24-1.05 (m, 1H); MS (ES) 397 (M+H).

Example 22:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-chloropyrimidin-2-ylamino)-2-methylbenzonitrile(Compound 40)

Compound 40 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.37 (s, 1H), 8.12 (d, J=2.2 Hz, 1H), 7.88-7.75(m, 1H), 7.72-7.61 (m, 1H), 7.26 (d, J=8.8 Hz, 1H), 3.65-3.47 (m, 4H),2.73 (d, J=9.7 Hz, 4H), 2.53-2.43 (m, 1H), 2.36 (s, 3H), 2.02-1.73 (m,4H), 1.72-1.56 (m, 2H), 1.58-1.23 (m, 4H), 1.24-1.02 (m, 1H); MS (ES)411 (M+H).

Example 23:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-chloropyrimidin-2-ylamino)-2-cyclopropylbenzonitrile(Compound 41)

Compound 41 was prepared as described for the corresponding formic acidsalt in Example 124.

¹H NMR (300 MHz, dmso) δ 9.36 (s, 1H), 8.08 (d, J=2.3 Hz, 1H), 7.91 (d,J=2.5 Hz, 1H), 7.81 (d, J=11.1 Hz, 1H), 7.67 (s, 1H), 6.93 (d, J=8.8 Hz,1H), 3.56 (t, J=5.4 Hz, 2H), 2.72 (d, J=10.6 Hz, 2H), 2.53-2.41 (m, 1H),2.14-1.99 (m, 2H), 1.99-1.69 (m, 5H), 1.65 (d, J=12.8 Hz, 2H), 1.60-1.21(m, 4H), 1.23-1.07 (m, 1H), 1.07-0.90 (m, 2H), 0.80-0.62 (m, 2H); MS(ES) 437 (M+H).

Example 24:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-chloropyrimidin-2-ylamino)-2-cyclopropyl-4-fluorobenzonitrile(Compound 42)

Compound 42 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 8.74 (s, 1H), 8.10 (d, J=7.9 Hz, 1H), 7.88 (d,J=1.1 Hz, 1H), 7.62-7.45 (m, 1H), 6.96 (d, J=12.2 Hz, 1H), 3.58-3.22 (m,5H), 2.75 (m, 2H), 2.17-1.75 (m, 4H), 1.77-1.32 (m, 5H), 1.34-0.95 (m,5H), 0.81 (t, J=4.5 Hz, 2H); MS (ES) 455 (M+H).

Example 25:5-chloro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3,5-dimethoxyphenyl)pyrimidine-2,4-diamine(Compound 43, bis-trifluoroacetate salt)

Compound 43 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.81 (d, J=11.5 Hz, 1H), 9.69-9.23 (m, 1H),8.10-7.98 (m, 1H), 6.89 (d, J=2.2 Hz, 1H), 6.74 (d, J=2.2 Hz, 1H), 6.21(dt, J=6.2, 2.2 Hz, 1H), 3.70 (s, 6H), 3.56-3.24 (m, 3H), 3.22-3.08 (m,2H), 3.02-2.75 (m, 1H), 2.43-2.27 (m, 1H), 2.26-2.12 (m, 1H), 2.05-1.68(m, 7H), 1.67-1.51 (m, 6H), 1.51-1.17 (m, 2H); MS (ES) 432 (M+H).

Example 26:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-chloropyrimidin-2-ylamino)benzo[d]oxazol-2(3H)-one(Compound 44)

Compound 44 was prepared as described in Example 1.

MS (ES) 429 (M+H).

Example 27:N2-(5-(5-cyclopropyl-1H-tetrazol-1-yl)-2-fluorophenyl)-5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine(Compound 45)

Compound 45 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 8.67 (s, 1H), 8.40 (dt, J=6.8, 3.4 Hz, 1H),7.84 (d, J=3.7 Hz, 1H), 7.56 (s, 1H), 7.47 (dd, J=10.7, 8.8 Hz, 1H),7.30 (dt, J=7.6, 3.4 Hz, 1H), 3.40 (dd, J=11.0, 3.7 Hz, 3H), 2.64 (t,J=10.6 Hz, 3H), 2.11-1.96 (m, 1H), 1.87-1.68 (m, 4H), 1.68-1.51 (m, 3H),1.50-1.37 (m, 1H), 1.37-0.96 (m, 8H); MS (ES) 482 (M+H).

Example 28:N2-(4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine(Compound 46, bis-formate salt)

Compound 46 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.96 (s, 1H), 9.87 (d, J=14.3 Hz, 1H),9.08-8.66 (m, 1H), 8.15-8.00 (m, 1H), 7.90-7.76 (m, 1H), 7.26 (dd,J=11.6, 8.1 Hz, 1H), 6.24 (d, J=7.1 Hz, 1H), 3.57-3.05 (m, 4H),3.04-2.76 (m, 2H), 2.13-1.86 (m, 1H), 1.86-1.30 (m, 9H), 1.28-1.06 (m,3H), 0.84 (t, J=5.8 Hz, 2H), 0.77-0.61 (m, 2H); MS (ES) 464 (M+H).

Example 29:N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methyl-3-(1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine(Compound 47, formate salt)

Compound 47 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.58-10.29 (m, 1H), 9.88 (d, J=12.6 Hz, 1H),9.39-9.09 (m, 1H), 7.90-7.76 (m, 1H), 7.71-7.59 (m, 1H), 7.58-7.51 (m,1H), 6.29 (dd, J=7.1, 3.9 Hz, 1H), 3.45-3.06 (m, 2H), 3.06-2.75 (m, 3H),2.37-1.95 (m, 3H), 2.11 (s, 3H) 1.92-1.50 (m, 6H), 1.49-1.10 (m, 5H); MS(ES) 420 (M+H).

Example 30:1-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)pyrimidin-2-ylamino)-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one(Compound 48)

Compound 48 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 8.24 (d, J=0.8 Hz, 2H), 7.97 (d, J=7.6 Hz, 1H),7.71 (s, 1H), 7.24 (s, 1H), 6.97 (d, J=12.1 Hz, 1H), 5.94 (dd, J=5.9,0.7 Hz, 1H), 3.62 (s, 3H), 3.45-3.29 (m, 1H), 3.29-3.12 (m, 1H),3.03-2.81 (m, 2H), 2.51-2.13 (m, 3H), 1.86 (s br, 1H), 1.76-1.12 (m,11H), 0.81 (dt, J=5.5, 5.0 Hz, 2H), 0.70-0.55 (m, 2H); MS (ES) 494(M+H).

Example 31:N2-(4-fluoro-3-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine(Compound 49)

Compound 49 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.55-10.15 (m, 1H), 9.38-8.95 (m, 1H), 8.02(s, 1H), 7.91-7.75 (m, 2H), 7.75-7.58 (m, 2H), 6.27 (d, J=6.8 Hz, 1H),3.65-3.10 (m, 2H), 3.06-2.76 (m, 2H), 2.26 (s, 3H), 2.19-1.90 (m, 1H),1.90-1.52 (m, 6H), 1.51-1.12 (m, 3H); MS (ES) 438 (M+H).

Example 32:N2-(2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine(Compound 50, bis-trifluoroacetate salt)

Compound 50 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.73 (s, 1H), 9.40-9.12 (m, 1H), 8.30-7.72 (m,2H), 7.64 (dd, J=10.3, 4.8 Hz, 2H), 6.29 (t, J=7.5 Hz, 1H), 3.62-2.61(m, 7H), 2.29 (s, 3H), 2.17-1.83 (m, 2H), 1.85-0.92 (m, 9H); MS (ES) 438(M+H).

Example 33:N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methoxy-3-(5-methyl-1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine(Compound 51, bis-trifluoroacetate salt)

Compound 51 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 11.20-10.53 (m, 1H), 9.84 (s, 1H), 9.50-9.05(m, 1H), 7.98-7.50 (m, 3H), 7.50-7.23 (m, 1H), 6.22 (dd, J=7.0, 3.4 Hz,1H), 3.80 (s, 3H), 3.75-3.05 (m, 5H), 3.04-2.62 (m, 2H), 2.38 (s, 3H),2.21-1.97 (m, 1H), 1.87-1.06 (m, 10H); MS (ES) 450 (M+H).

Example 34:N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine(Compound 52, bis-trifluoroacetate salt)

Compound 52 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 11.33-10.96 (m, 1H), 9.42-9.24 (m, 1H), 7.87(t, J=8.1 Hz, 1H), 7.50 (s, 1H), 7.36 (s, 1H), 7.09 (s, 1H), 6.29 (d,J=7.2 Hz, 1H), 3.82 (s, 3H), 3.77-3.61 (m, 1H), 3.57-3.05 (m, 3H),3.05-2.77 (m, 2H), 2.58 (s, 3H), 2.48 (d, J=1.7 Hz, 1H), 2.31-2.02 (m,1H), 1.88-1.33 (m, 8H), 1.31-1.09 (m, 1H); MS (ES) 450 (M+H).

Example 35:3-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)pyrimidin-2-ylamino)benzonitrile(Compound 53, bis-trifluoroacetate salt)

Compound 53 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 11.15-10.79 (m, 1H), 10.01-9.57 (m, 1H), 9.20(s, 1H), 8.24-7.98 (m, 1H), 7.96-7.64 (m, 2H), 7.59 (s, 1H), 6.27 (d,J=7.1 Hz, 1H), 3.28-2.75 (m, 6H), 2.26 (m, 1H), 2.10 (m, 1H), 1.95-1.14(m, 10H); MS (ES) 463 (M+H).

Example 36:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)pyrimidin-2-ylamino)-2-methylbenzonitrile(Compound 54, bis-trifluoroacetate salt)

Compound 54 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 11.23-10.75 (m, 1H), 9.54-8.90 (m, 1H),8.24-7.91 (m, 1H), 7.86 (t, J=7.6 Hz, 1H), 7.61 (t, J=9.1 Hz, 1H), 7.45(d, J=8.5 Hz, 1H), 6.34-6.13 (m, 1H), 3.42-3.10 (m, 3H), 3.08-2.93 (m,2H), 2.95-2.79 (m, 2H), 2.44 (s, 3H), 2.33-2.18 (m, 1H), 2.09 (s, 1H),1.94-1.20 (m, 9H); MS (ES) 377 (M+H).

Example 37:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)pyrimidin-2-ylamino)-2-cyclopropylbenzonitrile(Compound 55, bis-trifluoroacetate salt)

Compound 55 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 11.09-10.62 (m, 1H), 9.56-8.95 (m, 1H),8.19-7.89 (m, 1H), 7.87-7.74 (m, 1H), 7.68-7.46 (m, 1H), 7.10 (d, J=8.8Hz, 1H), 6.26 (d, J=11.6 Hz, 1H), 3.24-2.72 (m, 4H), 2.34-2.00 (m, 3H),1.95-1.23 (m, 12H), 1.10 (d, J=7.9 Hz, 2H), 0.90-0.56 (m, 2H); MS (ES)403 (M+H).

Example 38:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)pyrimidin-2-ylamino)-2-cyclopropyl-4-fluorobenzonitrile(Compound 56, bis-formate salt)

Compound 56 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.06 (s, 1H), 9.42-9.10 (m, 1H), 8.23-8.02 (m,1H), 7.83 (dd, J=10.4, 7.4 Hz, 1H), 6.28 (t, J=6.4 Hz, 1H), 3.30-3.04(m, 4H), 3.05-2.73 (m, 2H), 2.22-2.07 (m, 2H), 2.00-1.87 (m, 2H),1.87-1.30 (m, 10H), 1.24-1.05 (m, 2H), 0.95-0.73 (m, 2H); MS (ES) 421(M+H).

Example 39:N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3,5-dimethoxyphenyl)pyrimidine-2,4-diamine(Compound 57, bis-formate salt)

Compound 57 was prepared as described in Example 1.

MS (ES) 398 (M+H).

Example 40:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)pyrimidin-2-ylamino)benzo[d]oxazol-2(3H)-one(Compound 58, bis-formate salt)

Compound 58 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 11.73 (s, 1H), 10.28-10.04 (m, 1H), 9.21-8.73(m, 1H), 7.75 (dd, J=7.1, 4.6 Hz, 1H), 7.28 (td, J=8.3, 2.7 Hz, 2H),7.21-7.13 (m, 1H), 6.31-6.11 (m, 1H), 3.34-3.06 (m, 4H), 3.03-2.69 (m,3H), 2.21-1.89 (m, 1H), 1.87-1.61 (m, 4H), 1.60-1.34 (m, 5H), 1.37-1.12(m, 2H); MS (ES) 495 (M+H).

Example 41:N2-(4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methylpyrimidine-2,4-diamine(Compound 59, bis-trifluoroacetate salt)

Compound 59 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.32-10.08 (m, 1H), 9.86 (dd, J=17.5, 2.3 Hz,1H), 9.24 (s, 1H), 8.52-8.19 (m, 1H), 7.97 (d, J=7.4 Hz, 1H), 7.82-7.73(m, 1H), 7.24 (t, J=11.0 Hz, 1H), 3.36-3.03 (m, 4H), 3.02-2.89 (m, 1H),2.90-2.75 (m, 1H), 2.18-2.03 (m, 1H), 1.96 (s, 3H), 1.84-1.25 (m, 10H),1.24-1.09 (m, 1H), 1.08-0.95 (m, 1H), 0.84 (t, J=8.0 Hz, 2H), 0.77-0.58(m, 2H); MS (ES) 478 (M+H).

Example 42:N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methyl-N2-(4-methyl-3-(1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine(Compound 60, bis-formate salt)

Compound 60 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.43-10.10 (m, 1H), 9.93-9.72 (m, 1H), 8.84(s, 1H), 8.50 (d, J=16.0 Hz, 1H), 7.79-7.68 (m, 1H), 7.65-7.51 (m, 2H),3.69-3.54 (m, 1H), 3.51-3.03 (m, 4H), 3.02-2.74 (m, 1H), 2.23-2.16 (m,1H), 2.12 (s, 3H), 1.98 (s, 3H), 1.87-1.51 (m, 7H), 1.42 (m, 3H),1.27-1.04 (m, 1H); MS (ES) 434 (M+H).

Example 43:1-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methylpyrimidin-2-ylamino)-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one(Compound 61, bis-formate salt)

Compound 61 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.94 (d, J=26.4 Hz, 1H), 9.24 (s, 1H), 8.75 (s,1H), 8.52 (d, J=23.2 Hz, 1H), 7.72 (t, J=8.2 Hz, 1H), 7.54 (d, J=8.8 Hz,1H), 3.61 (s, 3H), 3.55-3.37 (m, 1H), 3.36-3.00 (m, 4H), 3.00-2.86 (m,1H), 2.87-2.70 (m, 1H), 2.13-1.99 (m, 1H), 1.96 (s, 3H), 1.91-1.05 (m,11H), 1.00-0.86 (m, 2H), 0.83-0.65 (m, 2H); MS (ES) 508 (M+H).

Example 44:N2-(4-fluoro-3-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methylpyrimidine-2,4-diamine(Compound 62, formate salt)

Compound 62 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.70-10.11 (m, 1H), 8.67-8.41 (m, 1H),8.04-7.88 (m, 1H), 7.83-7.52 (m, 2H), 7.32 (t, J=9.5 Hz, 1H), 7.02-6.88(m, 1H), 3.41-3.20 (m, 3H), 3.20-3.02 (m, 2H), 3.02-2.71 (m, 2H), 2.44(s, 3H), 2.20-2.04 (m, 1H), 1.98 (s, 3H), 1.88-1.48 (m, 5H), 1.49-1.23(m, 4H), 1.23-0.98 (m, 1H); MS (ES) 452 (M+H).

Example 45:N2-(2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methylpyrimidine-2,4-diamine(Compound 63, formate salt)

Compound 63 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.11 (d, J=14.3 Hz, 1H), 8.81 (s, 1H),8.64-8.48 (m, 1H), 7.89 (d, J=7.0 Hz, 1H), 7.77 (d, J=15.2 Hz, 1H),7.70-7.60 (m, 1H), 3.44-3.35 (m, 2H), 3.34-3.17 (m, 2H), 3.09 (d, J=13.4Hz, 1H), 2.98-2.70 (m, 2H), 2.53 (td, J=4.2, 1.9 Hz, 2H), 2.21-2.03 (m,1H), 1.98 (s, 3H), 1.92 (s, 1H), 1.86-1.45 (m, 8H), 1.43-1.03 (m, 5H),1.01-0.81 (m, 1H); MS (ES) 452 (M+H).

Example 46:N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methoxy-3-(5-methyl-1H-tetrazol-1-yl)phenyl)-5-methylpyrimidine-2,4-diamine(Compound 64, bis-trifluoroacetate salt)

Compound 64 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 11.13-10.47 (m, 1H), 10.12-9.33 (m, 1H),8.66-8.34 (m, 1H), 7.93-7.48 (m, 2H), 7.38 (s, 1H), 3.80 (s, 3H),3.74-3.59 (m, 1H), 3.52-3.21 (m, 2H), 3.19-3.03 (m, 2H), 3.03-2.89 (m,1H), 2.89-2.68 (m, 1H), 2.38 (s, 3H), 2.30-2.16 (m, 1H), 2.13-2.01 (m,1H), 1.97 (s, 3H), 1.89-0.99 (m, 9H); MS (ES) 464 (M+H).

Example 47:N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-5-methylpyrimidine-2,4-diamine(Compound 65, bis-trifluoroacetate salt)

Compound 65 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 11.22-10.77 (m, 1H), 10.06-9.31 (m, J=128.3 Hz,1H), 8.73-8.42 (m, 1H), 7.82 (d, J=13.1 Hz, 1H), 7.47-7.16 (m, 2H),7.14-6.90 (m, 1H), 3.82 (s, 3H), 3.76 (d, J=8.0 Hz, 1H), 3.52-3.21 (m,2H), 3.21-3.05 (m, 2H), 3.02-2.90 (m, 1H), 2.84 (s, 1H), 2.58 (s, 3H),2.32 (m, 1H), 2.12 (d, J=6.1 Hz, 1H), 2.00 (s, 3H), 1.95-1.48 (m, 7H),1.48-1.09 (m, 2H); MS (ES) 464 (M+H).

Example 48:3-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methylpyrimidin-2-ylamino)benzonitrile(Compound 66, bis-formate salt)

Compound 66 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.17 (s, 1H), 8.23 (d, J=15.6 Hz, 2H), 7.96 (d,J=8.7 Hz, 1H), 7.66 (s, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.23 (d, J=7.2 Hz,1H), 6.91 (s, 1H), 2.87-2.70 (m, 4H), 2.21-1.92 (m, 3H), 1.90 (s, 3H),1.86-1.61 (m, 3H), 1.60-1.40 (m, 4H), 1.40-1.28 (m, 2H), 1.26-1.10 (m,2H); MS (ES) 377 (M+H).

Example 49:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methylpyrimidin-2-ylamino)-2-methylbenzonitrile(Compound 67, bis-formate salt)

Compound 67 was prepared as described in Example 1.

MS (ES) 391 (M+H).

Example 50:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methylpyrimidin-2-ylamino)-2-cyclopropylbenzonitrile(Compound 68, bis-formate salt)

Compound 68 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.27-10.05 (m, 1H), 9.38-8.81 (m, 1H), 8.49(d, J=14.4 Hz, 1H), 8.03-7.79 (m, 1H), 7.75 (d, J=11.1 Hz, 1H), 7.56 (t,J=10.3 Hz, 1H), 3.73-3.58 (m, 1H), 3.31-3.23 (m, 2H), 3.21-3.05 (m, 2H),3.04-2.74 (m, 1H), 2.21-2.06 (m, 1H), 1.98 (s, 3H), 1.93-1.63 (m, 6H),1.61-1.25 (m, 6H), 1.24-1.05 (m, 2H), 0.76 (t, J=9.0 Hz, 2H); MS (ES)417 (M+H).

Example 51:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methylpyrimidin-2-ylamino)-2-cyclopropyl-4-fluorobenzonitrile(Compound 69, bis-trifluoroacetate salt)

Compound 69 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.38 (s, 1H), 8.67-8.48 (m, 1H), 8.17-7.97 (m,1H), 7.79 (dd, J=10.5, 0.9 Hz, 1H), 7.13 (dd, J=11.9, 7.1 Hz, 1H),3.66-3.40 (m, 1H), 3.40-3.21 (m, 2H), 3.14 (d, J=7.5 Hz, 1H), 2.98 (d,J=12.0 Hz, 1H), 2.83 (s, 1H), 2.14 (t, J=12.8 Hz, 1H), 1.98 (s, 3H),1.87-1.28 (m, 11H), 1.16 (dd, J=10.6, 4.4 Hz, 2H), 1.04-0.77 (m, 3H); MS(ES) 435 (M+H).

Example 52:N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3,5-dimethoxyphenyl)-5-methylpyrimidine-2,4-diamine(Compound 70, bis-trifluoroacetate salt)

Compound 70 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.71-10.35 (m, 1H), 8.63-8.47 (m, 1H), 7.75(d, J=16.9 Hz, 1H), 6.77 (s, 1H), 6.61 (s, 1H), 6.35 (d, J=1.7 Hz, 1H),3.73 (s, 6H), 3.58-3.23 (m, 1H), 3.24-3.04 (m, 2H), 2.97 (d, J=11.0 Hz,1H), 2.92-2.69 (m, 1H), 2.41-2.26 (m, 1H), 2.23-2.04 (m, 1H), 1.98 (s,3H), 1.93-1.68 (m, 5H), 1.67-1.50 (m, 4H), 1.50-1.19 (m, 2H); MS (ES)412 (M+H).

Example 53:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methylpyrimidin-2-ylamino)benzo[d]oxazol-2(3H)-one(Compound 71, trifluoroacetate salt)

Compound 71 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 11.85 (t, J=7.0 Hz, 1H), 10.81-10.44 (m, 1H),9.97-9.31 (m, 1H), 8.66-8.36 (m, 1H), 7.81-7.61 (m, 1H), 7.34-6.97 (m,2H), 3.77-2.61 (m, 6H), 2.34-2.11 (m, 1H), 2.14-2.01 (m, 1H), 1.97 (s,3H), 1.93-1.60 (m, 4H), 1.61-1.45 (m, 3H), 1.46-0.99 (m, 3H); MS (ES)409 (M+H).

Example 54:N2-(4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methoxypyrimidine-2,4-diamine(Compound 72, bis-formate salt)

Compound 72 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.91-9.77 (m, 1H), 9.00 (dd, J=74.3, 56.6 Hz,2H), 8.00-7.73 (m, 1H), 7.63-7.50 (m, 1H), 7.33-7.17 (m, 1H), 3.82 (s,3H), 3.34-3.03 (m, 5H), 3.02-2.70 (m, 2H), 2.21-1.88 (m, 1H), 1.87-1.28(m, 9H), 1.24-0.92 (m, 2H), 0.86 (d, J=8.0 Hz, 2H), 0.79-0.62 (m, 2H);MS (ES) 494 (M+H).

Example 55:N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methoxy-N2-(4-methyl-3-(1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine(Compound 73)

Compound 73 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.84 (s, 1H), 9.00 (s, 1H), 8.05 (s, 1H), 7.73(d, J=8.4 Hz, 1H), 7.54 (s, 1H), 7.27 (d, J=8.5 Hz, 1H), 6.97 (t, J=5.4Hz, 1H), 3.72 (s, 3H), 3.55-3.35 (m, 4H), 2.69 (t, J=9.6 Hz, 3H),1.95-1.74 (m, 4H), 1.71-1.53 (m, 3H), 1.52-1.02 (m, 4H); MS (ES) 450(M+H).

Example 56:1-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methoxypyrimidin-2-ylamino)-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one(Compound 74)

Compound 74 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 8.10 (dt, J=18.9, 9.5 Hz, 1H), 8.02 (s, 1H),7.49 (s, 1H), 7.09-6.87 (m, 2H), 3.71 (s, 3H), 3.61 (s, 3H), 3.49-3.35(m, 4H), 2.67 (m, 3H), 1.91-1.72 (m, 4H), 1.72-1.51 (m, 5H), 1.52-1.00(m, 3H), 0.87-0.72 (m, 2H), 0.67-0.53 (m, 2H); MS (ES) 524 (M+H).

Example 57:N2-(4-fluoro-3-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methoxypyrimidine-2,4-diamine(Compound 75)

Compound 75 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.12 (s, 1H), 8.21 (dt, J=12.5, 6.3 Hz, 1H),7.87 (dd, J=8.4, 3.8 Hz, 1H), 7.54 (d, J=1.2 Hz, 1H), 7.41 (t, J=9.5 Hz,1H), 7.00 (t, J=5.2 Hz, 1H), 3.73 (s, 3H), 3.55-3.39 (m, 4H), 2.76-2.61(m, 3H), 2.48 (s, 3H), 1.94-1.72 (m, 4H), 1.72-1.53 (m, 3H), 1.54-1.02(m, 4H); MS (ES) 468 (M+H).

Example 58:N2-(2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methoxypyrimidine-2,4-diamine(Compound 76)

Compound 76 was prepared as described in Example 1.

MS (ES) 468 (M+H).

Example 59:N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methoxy-N2-(4-methoxy-3-(5-methyl-1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine(Compound 77)

Compound 77 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 8.84 (s, 1H), 8.01 (s, 1H), 7.85 (dd, J=9.1,1.7 Hz, 1H), 7.52 (s, 1H), 7.19 (d, J=9.2 Hz, 1H), 6.93 (t, J=5.1 Hz,1H), 3.71 (s, 3H), 3.42 (m, 3H), 3.31 (s, 3H), 2.69 (t, J=8.8 Hz, 4H),2.37 (s, 3H), 1.96-1.73 (m, 4H), 1.73-1.52 (m, 3H), 1.52-1.01 (m, 4H);MS (ES) 480 (M+H).

Example 60:N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methoxy-N2-(3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine(Compound 78)

Compound 78 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.07 (s, 1H), 7.66 (t, J=1.7 Hz, 1H), 7.62 (t,J=2.0 Hz, 1H), 7.56 (s, 1H), 6.97 (t, J=5.3 Hz, 1H), 6.67 (t, J=2.0 Hz,1H), 3.78 (s, 3H), 3.74 (s, 3H), 3.48 (td, J=14.0, 8.6 Hz, 2H),3.43-3.28 (m, 2H), 2.73-2.61 (m, 2H), 2.56 (s, 3H), 2.48 (dd, J=3.6, 1.8Hz, 1H), 1.93-1.69 (m, 4H), 1.68-1.53 (m, 3H), 1.51-1.03 (m, 4H); MS(ES) 480 (M+H).

Example 61:3-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methoxypyrimidin-2-ylamino)benzonitrile(Compound 79)

Compound 79 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.10 (s, 1H), 8.27 (d, J=1.5 Hz, 1H), 7.93 (d,J=7.5 Hz, 1H), 7.58 (s, 1H), 7.34 (t, J=8.0 Hz, 1H), 7.20 (d, J=7.5 Hz,1H), 7.03 (t, J=4.8 Hz, 1H), 3.78-3.71 (m, 3H), 3.54 (t, J=5.6 Hz, 2H),3.40-3.24 (m, 2H), 2.72 (d, J=10.8 Hz, 2H), 2.55-2.43 (m, 1H), 1.98-1.87(m, 2H), 1.87-1.72 (m, 3H), 1.72-1.59 (m, 2H), 1.57-1.33 (m, 4H),1.33-1.04 (m, 3H); MS (ES) 393 (M+H).

Example 62:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methoxypyrimidin-2-ylamino)-2-methylbenzonitrile(Compound 80)

Compound 80 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 8.95 (d, J=2.8 Hz, 1H), 8.21 (s, 1H), 7.81 (dd,J=8.5, 2.5 Hz, 1H), 7.56 (d, J=3.5 Hz, 1H), 7.21 (dd, J=8.6, 2.9 Hz,1H), 7.05-6.93 (m, 1H), 3.79-3.70 (s, 3H), 3.63-3.45 (m, 2H), 3.41-3.26(m, 2H), 2.71 (d, J=9.8 Hz, 2H), 2.56-2.44 (m, 1H), 2.35 (s, 3H),1.99-1.59 (m, 5H), 1.59-1.34 (m, 4H), 1.32-1.02 (m, 2H); MS (ES) 407(M+H).

Example 63:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methoxypyrimidin-2-ylamino)-2-cyclopropylbenzonitrile(Compound 81)

Compound 81 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 8.94 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.79 (d,J=8.8 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.01 (d, J=5.2 Hz, 1H), 6.90 (d,J=8.7 Hz, 1H), 3.73 (s, 3H), 3.52 (t, J=5.6 Hz, 2H), 3.42-3.22 (m, 2H),2.71 (d, J=10.2 Hz, 3H), 2.10-1.98 (m, 1H), 1.98-1.59 (m, 4H), 1.58-1.33(m, 4H), 1.32-1.05 (m, 3H), 1.00 (dd, J=6.4, 1.9 Hz, 2H), 0.68 (d, J=4.9Hz, 2H); MS (ES) 433 (M+H).

Example 64:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methoxypyrimidin-2-ylamino)-2-cyclopropyl-4-fluorobenzonitrile(Compound 82, bis-trifluoroacetate salt)

Compound 82 was prepared as described in Example 1.

MS (ES) 451 (M+H).

Example 65:N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-5-methoxy-N2-(3,5-dimethoxyphenyl)pyrimidine-2,4-diamine(Compound 83, bis-trifluoroacetate salt)

Compound 83 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.87-10.42 (m, 1H), 8.98 (d, J=5.8 Hz, 1H),7.64 (dd, J=17.1, 1.0 Hz, 1H), 6.77 (s, 1H), 6.62 (s, 1H), 6.32 (s, 1H),3.81 (s, 3H), 3.72 (s, 6H), 3.56-3.06 (m, 4H), 3.03-2.76 (m, 2H),2.44-2.27 (m, 1H), 2.25-2.08 (m, 1H), 2.04-1.14 (m, 10H); MS (ES) 428(M+H).

Example 66:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-methoxypyrimidin-2-ylamino)benzo[d]oxazol-2(3H)-one(Compound 84, bis-trifluoroacetate salt)

Compound 84 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 11.79 (d, J=6.1 Hz, 1H), 10.81-10.38 (m, 1H),9.80-9.24 (m, 1H), 9.03-8.79 (m, J=17.3 Hz, 1H), 7.70-7.53 (m, 1H),7.36-7.17 (m, 1H), 7.08 (dd, J=13.8, 5.2 Hz, 1H), 3.80 (s, 3H),3.67-3.02 (m, 4H), 2.99-2.62 (m, 2H), 2.36-2.16 (m, 1H), 2.14-2.00 (m,1H), 1.99-1.03 (m, 10H); MS (ES) 425 (M+H).

Example 67:N2-(4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N5,N5-dimethylpyrimidine-2,4,5-triamine(Compound 85, bis-formate salt)

Compound 85 was prepared as described in Example 1.

MS (ES) 507 (M+H).

Example 68:N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N5,N5-dimethyl-N2-(4-methyl-3-(1H-tetrazol-1-yl)phenyl)pyrimidine-2,4,5-triamine(Compound 86, bis-formate salt)

Compound 86 was prepared as described in Example 1.

MS (ES) 463 (M+H).

Example 69:1-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(dimethylamino)pyrimidin-2-ylamino)-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H-one(Compound 87, bis-formate salt)

Compound 87 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 8.45 (s, 1H), 8.13-7.75 (m, 1H), 7.66 (s, 1H),7.40-7.13 (m, 1H), 7.00 (d, J=12.0 Hz, 1H), 3.61 (s, 3H), 3.55-3.04 (m,3H), 3.00-2.74 (m, 4H), 2.52 (s, 6H), 2.23-1.98 (m, 4H), 1.95-1.44 (m,5H), 1.36 (s, 3H), 0.84 (s, 2H), 0.64 (s, 2H); MS (ES) 537 (M+H).

Example 70:N2-(4-fluoro-3-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N5,N5-dimethylpyrimidine-2,4,5-triamine(Compound 88, bis-formate salt)

Compound 88 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.21 (s, 1H), 8.24 (dd, J=7.1, 2.8 Hz, 1H),7.93-7.82 (m, 1H), 7.67 (d, J=2.7 Hz, 1H), 7.49-7.35 (m, 1H), 7.09 (d,J=7.7 Hz, 1H), 3.51-3.40 (m, 4H), 2.83-2.67 (m, 3H), 2.48 (s, 6H), 2.26(s, 3H), 2.08-1.82 (m, 3H), 1.82-1.54 (m, 3H), 1.54-1.02 (m, 5H); MS(ES) 481 (M+H).

Example 71:N2-(2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N5,N5-dimethylpyrimidine-2,4,5-triamine(Compound 89, bis-formate salt)

Compound 89 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.09-9.98 (m, 1H), 8.89-8.65 (m, 2H),8.18-7.86 (m, 1H), 7.74-7.54 (m, 2H), 3.29-3.14 (m, 3H), 3.15-3.01 (m,2H), 2.97-2.73 (m, 2H), 2.53 (s, 6H), 2.26 (s, 3H), 2.21-1.78 (m, 2H),1.76-0.81 (m, 10H); MS (ES) 481 (M+H).

Example 72:N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methoxy-3-(5-methyl-1H-tetrazol-1-yl)phenyl)-N5,N5-dimethylpyrimidine-2,4,5-triamine(Compound 90, bis-formate salt)

Compound 90 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.20-9.81 (m, 1H), 8.89-8.59 (m, 1H), 7.76 (d,J=2.5 Hz, 1H), 7.65 (dt, J=9.0, 3.3 Hz, 1H), 7.53 (dd, J=11.2, 8.7 Hz,2H), 7.37 (d, J=9.0 Hz, 1H), 3.80 (s, 3H), 3.34-3.19 (m, 3H), 3.20-3.03(m, 2H), 2.95 (d, J=11.6 Hz, 1H), 2.91-2.72 (m, 1H), 2.53 (s, 6H), 2.26(s, 3H), 2.15-1.96 (m, 3H), 1.96-1.43 (m, 6H), 1.43-0.99 (m, 2H); MS(ES) 493 (M+H).

Example 73:N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-N5,N5-dimethylpyrimidine-2,4,5-triamine(Compound 91, bis-formate salt)

Compound 91 was prepared as described in Example 1.

MS (ES) 493 (M+H).

Example 74:3-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(dimethylamino)pyrimidin-2-ylamino)benzonitrile(Compound 92, bis-formate salt)

Compound 92 was prepared as described in Example 1.

MS (ES) 406 (M+H).

Example 75:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(dimethylamino)pyrimidin-2-ylamino)-2-methylbenzonitrile(Compound 93, bis-formate salt)

Compound 93 was prepared as described in Example 1.

MS (ES) 420 (M+H).

Example 76:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(dimethylamino)pyrimidin-2-ylamino)-2-cyclopropylbenzonitrile(Compound 94, bis-trifluoroacetate salt)

Compound 94 was prepared as described in Example 1.

MS (ES) 446 (M+H).

Example 77:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(dimethylamino)pyrimidin-2-ylamino)-2-cyclopropyl-4-fluorobenzonitrile(Compound 95, bis-trifluoroacetate salt)

Compound 95 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.63-10.42 (m, 1H), 8.88-8.68 (m, 1H),8.21-7.98 (m, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.11 (dd, J=11.8, 6.8 Hz,1H), 3.61-3.40 (m, 1H), 3.42-3.20 (m, 3H), 3.21-3.03 (m, 2H), 3.03-2.72(m, 1H), 2.54 (s, 6H), 2.33-2.07 (m, 2H), 2.07-1.24 (m, 10H), 1.25-1.07(m, 2H), 1.04-0.79 (m, 2H); MS (ES) 464 (M+H).

Example 78:N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3,5-dimethoxyphenyl)-N5,N5-dimethylpyrimidine-2,4,5-triamine(Compound 96, bis-trifluoroacetate salt)

Compound 96 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.88-10.42 (m, 1H), 8.85-8.58 (m, 1H), 7.69(dd, J=13.2, 1.5 Hz, 1H), 6.79 (s, 1H), 6.62 (s, 1H), 6.32 (s, 1H), 3.73(s, 6H), 3.69-3.60 (m, 1H), 3.55-3.22 (m, 2H), 3.22-3.04 (m, 2H),3.04-2.73 (m, 2H), 2.53 (s, 6H), 2.45-2.28 (m, 1H), 2.26-2.09 (m, 1H),2.07-1.16 (m, 9H); MS (ES) 441 (M+H).

Example 79:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(dimethylamino)pyrimidin-2-ylamino)benzo[d]oxazol-2(3H)-one(Compound 97, bis-trifluoroacetate salt)

Compound 97 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 11.84 (s, 1H), 10.89-10.51 (m, 1H), 8.86-8.51(m, 1H), 7.67 (s, 1H), 7.24 (dd, J=14.0, 7.0 Hz, 2H), 7.08 (d, J=8.5 Hz,1H), 3.66-3.02 (m, 5H), 3.00-2.68 (m, 2H), 2.53 (s, 6H), 2.38-2.20 (m,1H), 2.18-2.01 (m, 1H), 2.00-1.47 (m, 6H), 1.48-1.01 (m, 3H); MS (ES)438 (M+H).

Example 80:4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(4-cyclopropyl-2-fluoro-5-(4,5-dihydro-4-methyl-5-oxotetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile(Compound 99)

Compound 99 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.41 (s, 1H), 8.25 (d, J=2.7 Hz, 1H), 8.18 (s,1H), 7.60 (dd, J=7.4, 2.4 Hz, 1H), 7.01 (dd, J=11.8, 2.1 Hz, 1H), 3.60(s, 3H), 3.49-3.32 (m, 2H), 3.49-3.33 (m, 3H), 2.79-2.60 (m, 2H),2.01-1.00 (m, 11H), 0.96-0.78 (m, 2H), 0.75-0.59 (m, 2H); MS (ES) 519(M+H).

Example 81:N2-(4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)phenyl)-5-(trifluoromethyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine(Compound 100, bis-formate salt)

Compound 100 was prepared as described in Example 1.

MS (ES) 532 (M+H).

Example 82:5-(trifluoromethyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methyl-3-(1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine(Compound 101, formate salt)

Compound 101 was prepared as described in Example 1.

MS (ES) 488 (M+H).

Example 83:1-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one(Compound 102, bis-formate salt)

Compound 102 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 8.64 (s, 1H), 8.19-8.08 (m, 1H), 7.71-7.59 (m,1H), 7.42-7.24 (m, 1H), 7.03 (d, J=11.3 Hz, 1H), 3.60 (s, 3H), 3.42-2.88(m, 4H), 2.50-2.33 (m, 3H), 2.19-1.86 (m, 2H), 1.85-1.06 (m, 10H),0.96-0.84 (m, 2H), 0.76-0.61 (m, 2H); MS (ES) 562 (M+H).

Example 84:N2-(4-fluoro-3-(5-methyl-1H-tetrazol-1-yl)phenyl)-5-(trifluoromethyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine(Compound 103, bis-trifluoroacetate salt)

Compound 103 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.63 (s, 1H), 9.30-9.03 (m, 1H), 8.39-8.23 (m,1H), 8.04-7.88 (m, 1H), 7.88-7.71 (m, 1H), 7.70-7.53 (m, 1H), 3.59-3.36(m, 1H), 3.36-3.19 (m, 2H), 3.20-2.67 (m, 4H), 2.49 (s, 3H), 2.26-1.97(m, 1H), 1.94-0.84 (m, 10H); MS (ES) 506 (M+H).

Example 85:N2-(2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-5-(trifluoromethyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine(Compound 104, bis-trifluoroacetate salt)

Compound 104 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.21-8.86 (m, 1H), 8.17-7.70 (m, 1H), 7.69-7.47(m, 1H), 7.21 (ddd, J=11.2, 8.6, 2.5 Hz, 1H), 6.95 (dt, J=7.8, 2.6 Hz,1H), 6.80-6.66 (m, 1H), 3.59-2.66 (m, 7H), 2.49 (s, 3H), 2.35-2.04 (m,1H), 1.98-1.19 (m, 6H), 1.17-0.92 (m, 3H), 0.87-0.65 (m, 1H); MS (ES)506 (M+H).

Example 86:5-(trifluoromethyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methoxy-3-(5-methyl-1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine(Compound 105, bis-trifluoroacetate salt)

Compound 105 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.53-9.33 (m, 1H), 8.73-8.47 (m, 1H), 8.38 (d,J=2.5 Hz, 1H), 7.75-7.59 (m, 2H), 7.36 (dd, J=8.7, 3.4 Hz, 2H), 3.81 (s,3H), 3.55-3.37 (m, 1H), 3.36-3.20 (m, 2H), 3.20-2.71 (m, 4H), 2.37 (s,3H), 2.21-1.84 (m, 1H), 1.84-1.04 (m, 9H), 0.90 (s, 1H); MS (ES) 518(M+H).

Example 87:5-(trifluoromethyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)phenyl)pyrimidine-2,4-diamine(Compound 106, bis-formate salt)

Compound 106 was prepared as described in Example 1.

MS (ES) 518 (M+H).

Example 88:3-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzonitrile(Compound 107, bis-formate salt)

Compound 107 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 8.69 (s, 1H), 8.31-8.16 (m, 1H), 8.08-7.95 (m,1H), 7.81 (s, 1H), 7.64-7.49 (m, 2H), 3.49-3.30 (m, 1H), 3.24-3.04 (m,3H), 3.01-2.70 (m, 1H), 2.44-2.23 (m, 2H), 2.22-1.26 (m, 11H); MS (ES)431 (M+H).

Example 89:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-methylbenzonitrile(Compound 108, bis-formate salt)

Compound 108 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 8.35-8.12 (m, 1H), 7.64 (t, J=11.8 Hz, 1H),7.46 (d, J=7.4 Hz, 1H), 7.38 (t, J=8.5 Hz, 1H), 7.07 (dd, J=13.7, 8.1Hz, 1H), 6.82-6.71 (m, 1H), 3.65-3.22 (m, 3H), 3.22-2.95 (m, 2H),2.90-2.62 (m, 2H), 2.26 (s, 3H), 2.23-2.12 (m, 1H), 2.12-1.77 (m, 4H),1.75-0.93 (m, 6H); MS (ES) 445 (M+H).

Example 90:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-cyclopropylbenzonitrile(Compound 109, bis-formate salt)

Compound 109 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 8.60 (s, 1H), 8.30-8.15 (m, 1H), 7.98-7.80 (m,1H), 7.80-7.58 (m, 1H), 7.45 (dd, J=8.0, 2.6 Hz, 1H), 7.13-6.99 (m, 1H),3.44-2.92 (m, 7H), 2.21-2.00 (m, 2H), 1.98-1.18 (m, 12H), 1.17-0.98 (m,2H), 0.85-0.67 (m, 2H); MS (ES) 471 (M+H).

Example 91:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-cyclopropyl-4-fluorobenzonitrile(Compound 110, bis-formate salt)

Compound 110 was prepared as described in Example 1.

MS (ES) 489 (M+H).

Example 92:5-(trifluoromethyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(3,5-dimethoxyphenyl)pyrimidine-2,4-diamine(Compound 111, bis-formate salt)

Compound 111 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 8.34-7.96 (m, 1H), 7.44 (s, 1H), 7.07 (s, 1H),6.78 (s, 1H), 6.28 (s, 1H), 3.71 (s, 3H), 3.61-2.96 (m, 4H), 2.95-2.56(m, 3H), 2.26 (s, 3H), 2.19-1.87 (m, 2H), 1.86-1.16 (m, 9H); MS (ES) 466(M+H).

Example 93:5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzo[d]oxazol-2(3H)-one(Compound 112, bis-formate salt)

Compound 112 was prepared as described in Example 1.

MS (ES) 463 (M+H).

Example 94:4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(4-methoxy-3-(5-methyl-1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile(Compound 113, bis-formate salt)

Compound 113 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.18-9.54 (m, 1H), 9.33-8.67 (m, 1H),8.42-8.27 (m, 1H), 7.99-7.69 (m, 2H), 7.37-7.19 (m, 1H), 3.77 (s, 3H),3.71-3.38 (m, 1H), 3.20-3.03 (m, 2H), 3.02-2.73 (m, 1H), 2.44-2.32 (m,3H), 2.26 (s, 3H), 2.21-2.02 (m, 2H), 1.99-1.03 (m, 9H); MS (ES) 475(M+H).

Example 95:4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(4-fluoro-3-(5-methyl-1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile(Compound 114, bis-formate salt)

Compound 114 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.29-9.82 (m, 1H), 9.32-8.70 (m, 1H),8.47-8.34 (m, 1H), 8.14-8.02 (m, 1H), 8.01-7.83 (m, 1H), 7.67-7.50 (m,1H), 3.62 (dd, J=4.4, 3.7 Hz, 1H), 3.54-3.22 (m, 4H), 3.23-3.05 (m, 1H),3.03-2.74 (m, 1H), 2.49 (s, 3H), 2.22-2.07 (m, 1H), 2.02-1.08 (m, 10H);MS (ES) 463 (M+H).

Example 96:4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile(Compound 115, bis-formate salt)

Compound 115 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.03 (s, 1H), 9.34-8.70 (m, 1H), 8.50-8.26 (m,1H), 7.99 (s, 1H), 7.59 (s, 1H), 7.04-6.88 (m, 1H), 3.79 (s, 3H),3.55-3.35 (m, 3H), 3.26-3.06 (m, 3H), 3.05-2.74 (m, 1H), 2.56 (s, 3H),2.38-2.14 (m, 3H), 2.03-1.07 (m, 8H); MS (ES) 475 (M+H).

Example 97:4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile(Compound 116, bis-formate salt)

Compound 116 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.95-9.76 (m, 1H), 9.71-9.40 (m, 1H), 8.33 (s,1H), 7.99-7.78 (m, 1H), 7.69 (d, J=6.1 Hz, 1H), 7.28-7.12 (m, 1H),3.58-3.40 (m, 1H), 3.37-3.00 (m, 3H), 3.00-2.72 (m, 3H), 2.19-1.94 (m,1H), 1.93-1.27 (m, 8H), 1.28-0.99 (m, 2H), 0.89-0.74 (m, 2H), 0.74-0.58(m, 2H); MS (ES) 489 (M+H).

Example 98:4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(4-methyl-3-(1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile(Compound 117)

Compound 117 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 10.12-9.76 (m, 1H), 8.41-8.24 (m, 1H), 7.96 (d,J=2.3 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.38 (d, J=8.6 Hz, 1H), 3.61-3.15(m, 3H), 2.85-2.56 (m, 4H), 2.06 (s, 3H), 1.99-0.99 (m, 11H); MS (ES)445 (M+H).

Example 99:4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile(Compound 118)

Compound 118 was prepared as described in Example 1.

¹H NMR (300 MHz, cdcl₃) δ 8.66 (d, J=5.1 Hz, 1H), 8.16 (s, 1H), 7.68 (d,J=8.1 Hz, 1H), 7.24 (d, J=9.2 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.00 (dd,J=7.5, 4.4 Hz, 1H), 3.70-3.48 (m, 3H), 3.39-2.98 (m, 4H), 2.27 (s, 3H),2.23-1.89 (m, 1H), 1.88-1.06 (m, 10H); MS (ES) 463 (M+H).

Example 100:4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(3-cyano-4-methylphenylamino)pyrimidine-5-carbonitrile(Compound 119)

Compound 119 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.91 (s, 1H), 8.33 (d, J=2.6 Hz, 2H), 8.08 (s,1H), 7.82 (dd, J=8.5, 2.2 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 3.70-3.44 (m,2H), 3.45-3.17 (m, 3H), 2.81-2.61 (m, 2H), 2.39 (s, 3H), 2.02-1.57 (m,6H), 1.56-1.23 (m, 4H), 1.23-1.02 (m, 1H); MS (ES) 402 (M+H).

Example 101:4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(3-cyano-4-cyclopropylphenylamino)pyrimidine-5-carbonitrile(Compound 120)

Compound 120 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.90 (s, 1H), 8.32 (d, J=1.7 Hz, 1H), 8.04 (s,1H), 7.83 (d, J=8.7 Hz, 1H), 6.99 (dd, J=8.7, 1.5 Hz, 1H), 3.67-3.45 (m,2H), 3.44-3.12 (m, 3H), 2.73 (d, J=10.2 Hz, 2H), 2.15-2.01 (m, 1H),2.01-1.56 (m, 6H), 1.56-1.24 (m, 4H), 1.24-1.10 (m, 1H), 1.05 (td,J=6.5, 1.9 Hz, 2H), 0.73 (t, J=5.5 Hz, 2H); MS (ES) 428 (M+H).

Example 102:4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(3,5-dimethoxyphenylamino)pyrimidine-5-carbonitrile(Compound 121)

Compound 121 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.63 (s, 1H), 8.39-8.16 (m, 2H), 7.00 (t, J=2.4Hz, 2H), 6.14 (t, J=2.2 Hz, 1H), 3.70 (s, 6H), 3.66-3.48 (m, 4H),2.82-2.62 (m, 3H), 2.06-1.57 (m, 6H), 1.56-1.26 (m, 4H), 1.25-1.03 (m,1H); MS (ES) 423 (M+H).

Example 103:4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(3-(5-cyclopropyl-1H-tetrazol-1-yl)-4-fluorophenylamino)pyrimidine-5-carbonitrile(Compound 122, bis-formate salt)

Compound 122 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 8.47-8.29 (m, 2H), 8.21-8.10 (m, 2H), 7.94 (dd,J=8.3, 3.9 Hz, 1H), 7.54 (t, J=9.5 Hz, 1H), 3.56-3.40 (m, 4H), 2.82-2.64(m, 3H), 2.10-1.99 (m, 1H), 1.98-1.77 (m, 4H), 1.77-1.23 (m, 7H),1.23-0.99 (m, 4H); MS (ES) 489 (M+H).

Example 104:4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(5-(5-cyclopropyl-1H-tetrazol-1-yl)-2-fluorophenylamino)pyrimidine-5-carbonitrile(Compound 123, bis-formate salt)

Compound 123 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.59 (s, 1H), 8.36-8.15 (m, 2H), 8.13-8.03 (m,1H), 7.56-7.48 (m, 2H), 3.46-3.23 (m, 3H), 2.68 (s, 4H), 2.02 (dd,J=10.6, 5.4 Hz, 1H), 1.96-1.69 (m, 4H), 1.70-1.39 (m, 4H), 1.39-0.95 (m,7H); MS (ES) 489 (M+H).

Example 105:4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(4-chloro-3-(5-cyclopropyl-1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile(Compound 124, bis-formate salt)

Compound 124 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 8.38 (t, J=7.7 Hz, 1H), 8.25-8.08 (m, 2H), 7.96(d, J=8.7 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 7.46 (d, J=6.8 Hz, 1H), 7.09(d, J=8.4 Hz, 1H), 3.37-2.85 (m, 5H), 2.33-2.20 (m, 2H), 2.17-1.99 (m,1H), 1.91-1.64 (m, 5H), 1.64-1.21 (m, 7H), 1.21-1.01 (m, 3H); MS (ES)506 (M+H).

Example 106:4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(4-methoxy-3-(5-methyl-1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carboxamide(Compound 125)

Compound 125 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.58 (s, 1H), 9.23 (s, 1H), 8.48 (s, 1H), 8.02(d, J=2.6 Hz, 1H), 7.88 (dd, J=9.1, 2.6 Hz, 1H), 7.24 (d, J=9.2 Hz, 1H),3.75 (s, 3H), 3.65-3.51 (m, 1H), 3.49-3.35 (m, 3H), 2.67 (t, J=10.4 Hz,3H), 2.38 (s, 3H), 1.92-1.73 (m, 2H), 1.72-1.40 (m, 4H), 1.39-1.00 (m,5H); MS (ES) 493 (M+H).

Example 107:4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(4-fluoro-3-(5-methyl-1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carboxamide(Compound 126)

Compound 126 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.78 (s, 1H), 9.22 (s, 1H), 8.47 (s, 1H), 8.20(dd, J=6.7, 2.6 Hz, 1H), 7.93-7.83 (m, 1H), 7.44 (t, J=9.5 Hz, 1H),3.60-3.46 (m, 1H), 3.46-3.20 (m, 4H), 2.72-2.56 (m, 2H), 2.45 (s, 3H),1.90-1.69 (m, 3H), 1.70-1.48 (m, 3H), 1.49-1.35 (m, 2H), 1.35-1.15 (m,2H), 1.15-0.95 (m, 1H); MS (ES) 481 (M+H).

Example 108:4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-2-(2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carboxamide(Compound 127, trifluoroacetate salt)

Compound 127 was prepared as described in Example 1.

¹H NMR (300 MHz, dmso) δ 9.18 (s, 2H), 8.49 (s, 1H), 8.22 (dd, J=6.9,2.5 Hz, 1H), 7.55-7.44 (m, 1H), 7.43-7.34 (m, 1H), 3.58-3.44 (m, 1H),3.33-3.06 (m, 2H), 2.81-2.63 (m, 4H), 2.55 (s, 3H), 2.07-1.80 (m, 3H),1.75-1.40 (m, 4H), 1.38-1.01 (m, 4H); MS (ES) 481 (M+H).

Example 109:1-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-2-cyclopropyl-4-methylphenyl)-4-methyl-1H-tetrazol-5(4H)-one(Compound 15)

Compound 15 was prepared as described in Example 1.

¹H NMR (300 MHz; d₆-DMSO) δ 8.08 (s, 1H), 7.7 (d, J=3.9 Hz, 1H), 7.57(s, 1H), 7.38 (m, 1H), 6.93 (s, 1H), 3.61 (s, 3H), 3.37 (m, 1H), 2.65(m, 2H), 2.22 (s, 3H), 1.78-1.2 (m, 14H), 0.76 (d, J=8.1 Hz, 2H), 0.54(m, 2H); m/z=508.39 (M+H)⁺.

Example 110:7-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-4-isopropyl-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 16)

Compound 16 was prepared as described in Example 1.

¹H NMR (300 MHz; d₆-DMSO) δ 8.99 (s, 1H), 7.8 (d, J=3.9 Hz, 1H), 7.51(d, J=2.1 Hz 1H), 7.42 (m, 1H), 7.31 (d, J=9.0 Hz 1H), 7.08 (d, J=9.0Hz, 1H), 4.64 (m, 1H), 3.55 (m, 2H), 2.72 (m, 2H), 1.97-1.67 (m, 14H),1.4 (s, 3H), 1.38, (s, 3H), 1.31 (s, 3H), 1.30 (s, 3H); m/z=497.10(M+H)⁺, m/z=495.12 (M−H)⁻

Example 111:1-(3-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-5-methoxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one(Compound 17)

Compound 17 was prepared as described in Example 1.

¹H NMR (300 MHz; d₆-DMSO) δ 9.27 (s, 1H), 7.9 (s, 1H), 7.85 (d, J=3.6Hz, 1H), 7.49 (s, 1H), 7.41 (m, 1H), 6.95 (m, 1H), 3.76 (s, 3H), 3.59(m, 1H), 3.53 (m, 2H), 2.67 (d, J=10.2 Hz, 2H), 1.88-1.28 (m, 14H);m/z=484.26 (M+H)⁺.

Example 112:7-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-4-(cyclopropylmethyl)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 18)

Compound 18 was prepared as described in Example 1.

¹H NMR (300 MHz; d₆-DMSO) δ 8.99 (s, 1H), 7.81 (d, J=3.9 Hz, 1H), 7.52(s, 1H), 7.42 (m, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.048 (d, J=8.7 Hz, 1H),3.76 (d, J=6.6 Hz, 2H), 3.54 (s, 2H), 2.72 (d, J=10.5 Hz, 2H), 1.94 (m,2H), 1.82 (m, 2H), 1.68 (d, J=12.0 Hz, 2H), 1.48-1.27 (9H), 0.42 (m,2H), 0.3 (m, 2H); m/z=509.00 (M+H)⁺.

Example 113:5-fluoro-N2-(3-(trifluoromethyl)-4-morpholinophenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine(Compound 19)

Compound 19 was prepared as described in Example 1.

¹H NMR (300 MHz; d₆-DMSO) δ 9.2 (s, 1H), 8.02 (s, 1H), 7.97 (d, J=9.3Hz, 1H), 7.83 (d, J=3.3 Hz, 1H), 7.49 (m, 1H), 7.4 (d, J=9.3 Hz, 1H),3.66 (s, 4H), 3.54 (m, 2H), 2.76 (s, 4H), 2.69 (m, 2H), 2.22 (s, 3H),1.90-1.17 (m, 14H); m/z=509.27 (M+H)⁺.

Example 114:5-fluoro-N2-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-7-yl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine(Compound 20)

Compound 20 was prepared as described in Example 1.

¹H NMR (300 MHz; d₆-DMSO) δ 9.36 (s, 1H), 8.08 (d, J=2.4 Hz, 1H), 7.85(d, J=3.6 Hz, 1H), 7.55 (m, 1H), 7.38 (d, J=6.6 Hz, 1H), 7.28 (s, 1H),3.56 (d, J=5.1 Hz, 2H), 2.71 (d, J=10.2 Hz, 2H), 1.92-1.2 (m, 14H); ¹⁹FNMR δ−90.94, −166.2; m/z=486.2 (M+H)⁺.

Example 115:5-fluoro-N2-(3-fluoro-5-methoxyphenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine(Compound 21)

Compound 21 was prepared as described in Example 1.

¹H NMR (300 MHz; d₆-DMSO) δ 9.15 (s, 1H), 7.85 (d, J=1.8 Hz, 1H), 7.48(m, 1H), 7.30 (d, J=11.7 Hz, 1H), 7.13 (s, 1H), 6.27 (d, J=8.4 Hz, 1H),3.72 (s, 3H), 3.63 (m, 2H), 2.7 (d, J=9.0 Hz, 2H), 1.93-1.2 (m, 14H),¹⁹F NMR δ−112.14, −166.5; m/z=404.23 (M+H)⁺.

Example 116:5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-N2-(4-methoxy-3-(oxazol-5-yl)phenyl)pyrimidine-2,4-diamine(Compound 22)

Compound 22 was prepared as described in Example 1.

¹H NMR (300 MHz; d₆-DMSO) δ 8.91 (s, 1H), 8.39 (s, 1H), 8.1 (d, J=2.1Hz, 1H), 7.79 (d, J=3.9 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.48 (s, 1H),7.41 (m, 1H), 6.99 (d, J=9.0 Hz, 1H), 3.86 (s, 3H), 3.54 (m, 2H), 2.65(m, 2H), 1.85-1.26 (m, 14H); m/z=453.31 (M+H)⁺.

Example 117:N2-(4-cyclopropyl-2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine(Compound 23)

Compound 23 was prepared as described in Example 1.

¹H NMR (300 MHz; d₆-DMSO) δ 8.54 (s, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.78(d, J=3.6 Hz, 1H), 7.46 (s, 1H), 7.05 (d, J=11.7 Hz, 1H), 3.37 (m, 2H),2.71 (m, 2H), 2.67 (m, 2H), 2.41 (s, 3H), 1.82-1.12 (m, 14H), 0.75 (m,2H), 0.65 (m, 2H); m/z=496.24 (M+H)⁺.

Example 118:N2-[3-(1,1-dioxo-isothiazolidin-2-yl)-4-fluoro-phenyl]-5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-pyrimidine-2,4-diamine(Compound 24)

Compound 24 was prepared as described in Example 1.

¹H NMR (300 MHz; d₆-DMSO) δ 9.07 (s, 1H), 8.54 (s, 1H), 8.21 (s, 1H),7.76 (d, J=7.5 Hz, 1H), 7.71-7.66 (m, 1H), 7.46 (m, 1H), 7.1 (t, J=9.3Hz, 1H), 3.71 (t, J=6.6 Hz, 2H), 3.5 (m, 2H), 3.37 (t, J=7.5 Hz, 2H),2.31 (d, J=11.7 Hz, 2H), 2.41 (t, J=7.2 Hz, 2H), 1.94-1.27 (m, 14H);m/z=493.32 (M+H)⁺.

Example 119:7-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-4-(3-fluoropropyl)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 25)

Compound 25 was prepared as described in Example 1.

¹H NMR (300 MHz; d₆-DMSO) δ 9.0 (s, 1H), 7.8 (d, J=3.0 Hz, 1H), 7.54 (s,1H), 7.42 (m, 1H), 7.31 (d, J=8.4 Hz, 1H), 6.97 (d, J=9.0 Hz, 1H), 4.55(t, J=5.7 Hz, 2H), 4.39 (t, J=5.4 Hz, 2H), 3.94 (t, J=6.9 Hz, 2H), 3.55(m, 2H), 2.70 (m, 2H), 1.97-1.29 (m, 17H), ¹⁹F NMR δ−73.4, −167.4;m/z=515.36 (M+H)⁺.

Example 120:7-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-4-(cyclopropylmethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 26)

Compound 26 was prepared as described in Example 1.

¹H NMR (300 MHz; d₆-DMSO) δ 9.0 (s, 1H), 7.81 (d, J=3.9 Hz, 1H),7.5-7.36 (m, 3H), 7.09 (d, J=8.7 Hz, 1H), 4.55 (s, 2H), 3.76 (m, 2H),3.54 (m, 2H), 2.70 (m, 2H), 1.78-1.2 (m, 14H), 0.425 (m, 2H), 0.31 (m,2H); m/z=481.26 (M+H)⁺.

Example 121:7-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-4-ethyl-2,2-difluoro-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one(Compound 27)

Compound 27 was prepared as described in Example 1.

¹H NMR (300 MHz; d₆-DMSO) δ 9.49 (s, 1H), 8.56 (d, J=2.4 Hz, 1H), 8.28(d, J=2.4 Hz, 1H), 7.87 (d, J=3.6 Hz, 1H), 7.65 (m, 1H), 4.09 (q, J=7.2Hz, 2H), 3.58 (m, 2H), 2.72 (d, J=10.5 Hz, 2H), 1.95-1.26 (m, 14H), 1.19(t, J=6.6 Hz, 2H), ¹⁹F NMR δ−73.9, −165.9; m/z=492.35 (M+H)⁺.

Example 122:N2-(5-(1-methyl-1H-tetrazol-5-yloxy)-4-cyclopropyl-2-fluorophenyl)-5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine(Compound 28, formate salt)

Compound 28 was prepared as described in Example 1.

¹H NMR (300 MHz; d₆-DMSO) δ 8.23 (m, 1H), 7.77 (s, 1H), 7.27 (s, 1H),3.51 (bs, 2H), 4.2 (s, 3H), 3.51 (s, 3H), 3.17 (d, J=11.7 Hz, 2H),1.98-1.36 (m, 14H), 0.86 (d, J=8.4 Hz, 2H), 0.64 (d, J=5.1 Hz, 2H);m/z=512.29 (M+H)⁺.

Example 123:5-fluoro-N2-(3-pentafluorosulfanyl-6-fluoro-phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine(Compound 29)

Compound 29 was prepared as described in Example 1.

Mono-SNAr product (75 mg, 1.0 eq), 3 ml of isopropyl alcohol,p-Toluenesulfonic acid monohydrate (1.5 eq) and the desired aniline (1.5eq) were used and the reaction was heated at 70° C. overnight. Afterpurification by preparative HPLC, the mixture was partitioned between 1MNaOH (30 mL) and EtOAc (30 mL). The aqueous layer was extracted withEtOAc (2×20 mL) and the combined organic extracts were dried (Na₂SO₄),filtered and the solvent removed under vacuum to leave a crude residue.The residue was lyophilized from MeCN/H₂O to give the product as asolid. Compound 29 was obtained as a single enantiomer (and singlediastereomer); purity=99.26% by LC/MS; m/z=500.29 (M+H)⁺. ¹H NMR (300MHz; d₆-DMSO) δ 8.72 (s, 1H), 8.46 (dd, J=6.9, 2.7 Hz, 1H), 7.83 (d,J=3.8 Hz, 1H), 7.58-7.53 (m, 2H), 7.40 (q, J=13.8 Hz, 1H), 3.43 (t,J=5.9 Hz, 2H), 2.74-2.62 (m, 2H), 1.91-1.55 (m, 7H), 1.49-1.06 (m, 7H);¹⁹F NMR (300 MHz; d₆-DMSO) δ−112.6 (m), −117.2, −135.1, −135.6, −166.2;m/z=500.29 (M+H)⁺.

Example 124:5-fluoro-N2-(3-pentafluorosulfanyl-5-fluoro-phenyl)-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidine-2,4-diamine(Compound 30)

Compound 30 was prepared as described in Example 1.

Mono-SNAr product (75 mg, 1.0 eq), 3 ml of isopropyl alcohol,p-Toluenesulfonic acid monohydrate (1.5 eq) and the desired aniline (1.5eq) were used and the reaction was heated at 70° C. overnight. Afterpurification by preparative HPLC, the mixture was partitioned between 1MNaOH (30 mL) and EtOAc (30 mL). The aqueous layer was extracted withEtOAc (2×20 mL) and the combined organic extracts were dried (Na₂SO₄),filtered and the solvent removed under vacuum to leave a residue. Theresidue was lyophilized from MeCN/H₂O to give the product (73 mg, 58%)as a solid. Compound 30 was obtained as a single enantiomer (and singlediastereomer); purity=99.67% by LC/MS; m/z=500.29 (M+H)⁺. ¹H NMR (300MHz; d₆-DMSO) δ 9.63 (s, 1H), 8.13 (d, J=11.8 Hz, 1H), 8.06 (s, 1H),7.91 (d, J=3.7 Hz, 1H), 7.63 (br. d, J=5.1 Hz, 1H), 7.27 (dt, J=8.9, 1.9Hz, 1H), 3.51-3.58 (m, 2H), 2.74 (br. d, J=10.6 Hz, 2H), 1.93-1.65 (m,7H), 1.45-1.13 (m, 7H); ¹⁹F NMR (300 MHz; d₆-DMSO) δ−109.7 (t), −113.7(m), −136.1, −136.7, −165.1; m/z=500.29 (M+H)⁺.

Example 125:7-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-4-(cyclopropylmethyl)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one(Compound 31)

Compound 31 was prepared as described in Example 1.

¹H NMR (300 MHz; d₆-DMSO) δ 9.19 (s, 1H), 8.38 (d, J=2.4 Hz, 1H), 7.84(d, J=3.6 Hz, 1H), 7.52 (s, 1H), 4.07 (d, J=5.4 Hz, 1H), 3.86 (d, J=6.9Hz, 2H), 3.56 (m, 1H), 3.15 (d, J=4.5 Hz, 2H), 2.7 (m, 2H), 1.95-1.2 (m,14H), 1.4 (s, 6H), 0.38 (m, 2H), 0.3 (m, 2H); m/z=509.99 (M+H)⁺.

Example 126: General Scheme for the Preparation of5-(4-(((1S,9aR)-octahydro-1H-quinolizin-9-yl)methylamino)-5-chloropyrimidin-2-ylamino)-2-cyclopropylbenzonitrile(Compound 5, formate salt)

Preparation of 2,5-dichloropyrimidin-4-ol

2,4,5-trichloropyrimidine (16.7 g, 91.0 mmol) was added to a tared,sealed flask and weighed. The oil was dissolved in 54 mL THF and cooledto 0° C. 1M aqueous NaOH solution (182 mL, 182 mmol) was added dropwisevia an addition funnel, keeping the reaction at 0° C. This was allowedto warm to room temperature and concentrated to remove THF. Additionalwater was added to maintain dissolution. The pH was adjusted to 6 with asmall quantity of HCl, and the aqueous was washed 3 times with ethylacetate. The pH was then brought below 1 with more HCl, and extractedsix times with ethyl acetate. This layer was washed with brine and driedover sodium sulfate. Product solution was filtered, concentrated, anddried on the high vacuum to give 14.1 g of 2,5-dichloropyrimidin-4-ol asan oil (96%).

¹H NMR (300 MHz; d₆-DMSO) δ 8.24 (s, 1H); m/z=165 (M+H)⁺.

Preparation of 5-amino-2-cyclopropylbenzonitrile

5-amino-2-bromobenzonitrile (5.0 g, 25.4 mmol), cyclopropylboronic acid(4.36 g, 50.8 mmol), Cs₂CO₃ (49.62 g, 152.3 mmol), andtricyclohexylphosphine (2.85 g, 10.2 mmol) were weighed out and added toa large reaction tube with magnetic stir bar. Toluene (120 mL) and water(40 mL) were added, and the reaction was subjected to vigoroussub-surface nitrogen sparging. Pd(OAc)₂ (1.14 g, 5.1 mmol) was weighedout and added, the tube was sealed under nitrogen, and the reaction washeated overnight at 110° C. This was then filtered with water and ethylacetate washings. The combined washings were treated with saturatedaqueous NaHCO₃ and the layers were separated. The aqueous was extracted4 more times with ethyl acetate, and the combined organic layer waswashed twice with brine and dried over sodium sulfate. After filtration,concentration, and drying on the high vacuum, 7.65 g was obtained of5-amino-2-cyclopropylbenzonitrile containing tricyclohexylphosphinederived byproducts. This was used without further purification.

¹H NMR (300 MHz; d₆-DMSO) δ 6.94-6.58 (m, 3H), 5.34 (s, 2H), 1.98-1.90(m, 1H), 0.91 (qd, 2H), 0.73-0.43 (m, 2H); m/z=159 (M+H)⁺.

Preparation of5-(5-chloro-4-hydroxypyrimidin-2-ylamino)-2-cyclopropylbenzonitrile

5-amino-2-cyclopropylbenzonitrile (25.4 mmol; from the previousreaction) was transferred to a large reaction tube with magnetic stirbar in 250 mL isopropyl alcohol. 2,5-dichloropyrimidin-4-ol (4.20 g,25.5 mmol) and p-toluenesulfonic acid monohydrate (14.50 g, 76.2 mmol)were weighed out and added. This was heated overnight at 110° C. Afterthat time, it was allowed to cool to room temperature and an orangeprecipitate was filtered off. The filtrate was concentrated to halfvolume, and a second precipitate crashed out which was filtered off.Again, the filtrate was concentrated to half volume and a thirdprecipitate crashed out which was filtered off. Finally, furtherconcentration crashed out a fourth precipitate which was collected andwashed with hexane. This was dried on high vacuum to give 5.63 g of5-(5-chloro-4-hydroxypyrimidin-2-ylamino)-2-cyclopropylbenzonitrile as atosylate salt, containing 1.2 equivalents of p-toluenesulfonic acid (45%yield).

¹H NMR (300 MHz; d₆-DMSO) δ 8.03 (d, 1H), 7.99 (s, 1H), 7.62 (dd, 1H),7.47 (d, 2.4H-tosylate), 7.11 (d, 2.4H-tosylate), 7.05 (d, 1H), 2.27 (s,3.6H-tosylate), 2.09 (td, 1H), 1.10-1.00 (m, 2H), 0.84-0.65 (m, 2H);m/z=287 (M+H)⁺.

Preparation of5-(4,5-dichloropyrimidin-2-ylamino)-2-cyclopropylbenzonitrile

5-(5-chloro-4-hydroxypyrimidin-2-ylamino)-2-cyclopropylbenzonitrile,containing 1.2 equivalents of p-toluenesulfonic acid (1.00 g, 2.03 mmol)was weighed out and added to a flask with a magnetic stir bar. This wassuspended in 11 mL POCl₃ and the reaction was heated at reflux for 3hours. This was evaporated, then quenched with cold 10% aqueous Na₂CO₃.The mixture was extracted 4 times with ethyl acetate and the combinedorganic layer was dried over sodium sulfate. This was filtered,concentrated onto a plug of silica, and purified by columnchromatography. Pure product was concentrated and dried on the highvacuum to give 493 mg of5-(4,5-dichloropyrimidin-2-ylamino)-2-cyclopropylbenzonitrile (80%yield, accounting for the mass of p-toluenesulfonic acid present in thestarting material).

¹H NMR (300 MHz; d₆-DMSO) δ 10.40 (s, 1H), 8.67 (s, 1H), 8.04 (d, 1H),7.76 (dd, 1H), 7.06 (d, 1H), 2.16-2.02 (m, 1H), 1.10-0.99 (m, 2H),0.84-0.71 (m, 2H); m/z=305 (M+H)⁺.

Preparation of5-(4-(((1S,9aR)-octahydro-1H-quinolizin-9-yl)methylamino)-5-chloropyrimidin-2-ylamino)-2-cyclopropylbenzonitrile(Compound 5, formate salt)

((1S,9aR)-octahydro-1H-quinolizin-9-yl)methanamine, di-HCl salt (55.4mg, 0.23 mmol) was weighed out and added to a reaction vial with amagnetic stir bar.5-(4,5-dichloropyrimidin-2-ylamino)-2-cyclopropylbenzonitrile (35.0 mg,0.12 mmol) was weighed out and added followed by addition of 3 mLisopropyl alcohol and then diisopropylethylamine (0.120 mL, 0.69 mmol).This was heated overnight at 110° C. The solvent was evaporated and theresidue purified by preparative HPLC to obtain 26.5 mg of pure Compound5 as a mono-formic acid salt (48% yield).

¹H NMR (300 MHz; d₆-DMSO) δ 9.37 (s, 1H), 8.17 (s, 1H), 8.10 (s, 1H),7.94 (s, 1H), 7.81 (dd, 1H), 7.64 (t, 1H), 6.96 (d, 1H), 3.56 (t, 2H),2.80 (d, 2H), 2.25-1.89 (m, 5H), 1.89-1.76 (m, 1H), 1.74-1.41 (m, 6H),1.35 (d, 2H), 1.20 (d, 1H), 1.02 (dt, 2H), 0.88-0.56 (m, 2H); m/z=437(M+H)⁺.

Example 127 Preparation1-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-2-(oxetan-3-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one(Compound 14)

To a microwave vial, was added2-chloro-5-fluoro-N-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidin-4-amine(prepared according to Example 1; 400 mg, 1.34 mmol, 1 equiv),1-(5-amino-2-(oxetan-3-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one(prepared as described in WO2011/068898, the disclosure of which isincorporated herein by reference; 493 mg, 1.87 mmol, 1.4 equiv),rac-BINAP (181 mg, 0.291 mmol, 0.217 equiv), Cs₂CO₃ (1.31 g, 4.02 mmol,3 equiv), Pd(OAc)₂ (26 mg, 0.116 mmol, 0.0870 equiv), and dioxane (10mL). The microwave vial was capped and sonicated under vacuum for 5 min.The reaction mixture was heated in the microwave at 120° C. for 2 h. Thecooled reaction mixture was filtered using a pad of celite and rinsedwith dioxane, and the filtrate was concentrated. The crude product waspurified by flash chromatography and eluted with DCM:2M NH₃/MeOH=100:0to 94:4 using 1% 2M NH₃/MeOH increments to provide the desired productCompound 141-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-2-(oxetan-3-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one(535 mg, 76%) as a solid.

¹H NMR (300 MHz; d₆-DMSO) δ 9.10 (s, 1H), 7.92 (s, 1H), 7.71-7.81 (m,2H), 7.45 (bs, 1H), 6.77-6.81 (d, 1H, J=9.3 Hz), 5.22-5.27 (p, 1H, J=4.8Hz), 4.80-4.84 (t, 2H, J=6 Hz), 4.40-4.44 (t, 2H, J=5.4 Hz), 3.62 (s,3H), 3.48 (bs, 2H), 2.69 (bs, 2H), 1.06-2.99 (m, 14H); ¹⁹F NMR (282 MHz;d₆-DMSO) δ−167.2 (s); m/z=526 (M+H)⁺.

Example 128: General Scheme for the Preparation ofN2-(4,4-dimethyl-4H-5-oxa-1,2,3,9b-tetraaza-cyclopenta[a]naphthalen-8-yl)-5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-pyrimidine-2,4-diamine(Compound 98)

Preparation of the nitro tetrazole(4,4-dimethyl-8-nitro-4H-benzo[b]tetrazolo[1,5-d][1,4]oxazine)

A suspension of 2,2-dimethyl-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one(1.00 g, 4.50 mmol, 1 equiv) and sodium azide (1.76 g, 27.0 mmol, 6equiv) in ACN (50 mL) under argon was cooled to −10° C. (externaltemperature). While maintaining the temperature at −10° C.,trifluoromethanesulfonic anhydride (2.27 mL, 3.81 g, 13.5 mmol, 3 equiv)was added slowly dropwise. The reaction was allowed to warm to RTovernight. TLC, LCMS indicated a 1:1 ratio of reactant:product. Reactionwas cooled to −10° C., and was slowly quenched with ice-cold saturatedNaHCO₃ and diluted with EtOAc. The layers were separated, and theorganic layer was washed with water 1×, dried over Na₂SO₄, andconcentrated to dryness. The crude product was purified by flashchromatography and eluted with DCM to afford the product nitro tetrazole(609 mg, 55%) as a white solid and recovered 450 mg of reactant.

¹H NMR (300 MHz; d₆-DMSO) δ 8.60-8.61 (d, 1H, J=2.4 Hz), 8.28-8.31 (m,1H), 7.46-7.49 (d, 1H, J=9 Hz), 1.83 (s, 3H); m/z=248 (M+H)⁺.

Preparation of the amine tetrazole(4,4-dimethyl-4H-benzo[b]tetrazolo[1,5-d][1,4]oxazin-8-amine)

A Parr vessel was charged with the nitro tetrazole (330 mg, 1.33 mmol),EtOH (4 mL), and 20% Pd(OH)₂/C (33 mg, 10% by weight of the startingnitro compound) giving a suspension. The vessel was sealed, degassed,and back-filled with H₂ (×3). The vessel was then charged with 40 psi H₂and allowed to shake for 3 h. LCMS analysis indicated a 10:90 ratio ofhydroxamine:product. Additional catalyst was added 20% Pd(OH)₂/C (33 mg,10% by weight of the starting nitro compound) and allowed to shake for 1h. LCMS analysis indicated a 10:90 ratio of hydroxamine:product. Thereaction mixture was filtered through a pad of celite, and the pad ofcelite was rinsed with MeOH. The filtrate was evaporated to dryness. Thecrude product was absorbed onto silica gel and purified by flashchromatography and eluted with hex:EtOAc=100:0 to 30%-40% EtOAc using10% EtOAc increments to afford the product amine tetrazole (269 mg, 93%)as a white solid.

¹H NMR (300 MHz; d₆-DMSO) δ 7.12-7.13 (d, 1H, J=2.7 Hz), 6.93-6.95 (d,1H, J=8.7 Hz), 6.58-6.61 (dd, 1H, J=2.4 Hz, J=8.7 Hz), 5.33 (bs, 2H),1.69 (s, 3H); m/z=218 (M+H)⁺.

Preparation ofN2-(4,4-dimethyl-4H-5-oxa-1,2,3,9b-tetraaza-cyclopenta[a]naphthalen-8-yl)-5-fluoro-N4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)-pyrimidine-2,4-diamine(Compound 98)

A mixture of2-chloro-5-fluoro-N-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidin-4-amine(prepared as described in Example 1; 42 mg, 0.142 mmol, 1 equiv), aminetetrazole (37 mg, 0.170 mmol, 1.2 equiv), and PTSA monohydrate (27 mg,1.42 mmol, 1 equiv) in IPA (2 mL) was heated to 70° C. for 3 d. LCMSindicated 1% unreacted2-chloro-5-fluoro-N-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidin-4-amine.After cooling the reaction to ambient temperature, 3-amino benzoic acid(20 mg, 0.142 mmol, 1 equiv) was added and heated to 70° C. overnight toscavenge the unreacted pyrimidine. After cooling to ambient temperature,the crude mixture was concentrated to dryness. The residue was taken inice-cold water, EtOAc, and aqueous 1N NaOH. The aqueous and organiclayers were partitioned, and the organic layer washed with 1N NaOH (1×5mL). The organic layer was dried (Na₂SO₄), filtered, and the solventremoved under vacuum. The crude product was purified by prepTLC usingDCM:2M NH₃/MeOH=1:1 to provide the desired product Compound 98 (56 mg,83%) as a solid.

¹H NMR (300 MHz; d₆-DMSO) δ 9.27 (s, 1H), 8.53 (s, 1H), 7.85-7.87 (m,1H), 7.51-7.61 (m, 2H), 7.07-7.15 (d, 1H, J=9 Hz), 3.49-3.58 (m, 2H),2.51-2.74 (m, 2H), 0.986-2.09 (m, 20H); ¹⁹F NMR (282 MHz; d₆-DMSO)δ−166.8 (s); m/z=480 (M+H)⁺.

Example 129:2-((2-fluoro-4-hydroxy-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile(Compound 128)

Compound 128 was prepared as described in Example 1.

MS (ES) 495 (M+H).

Example 130:2-((2-fluoro-4-(2-methoxyethoxy)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile(Compound 129, formate salt)

Compound 129 was prepared as described in Example 1.

MS (ES) 533 (M+H).

Example 131:2-((2-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)-4-((3-methyloxetan-3-yl)methoxy)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile(Compound 130, formate salt)

Compound 130 was prepared as described in Example 1.

MS (ES) 579 (M+H).

Example 132:2-((4-((1,4-dioxan-2-yl)methoxy)-2-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile(Compound 131, formate salt)

Compound 131 was prepared as described in Example 1.

MS (ES) 595 (M+H).

Example 133:2-((4-(2,3-dihydroxypropoxy)-2-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile(Compound 132, TFA salt)

Compound 132 was prepared as described in Example 1.

MS (ES) 569 (M+H).

Example 134:2-((2-fluoro-4-(2-(2-methoxyethoxyl)ethoxy)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile(Compound 133, formate salt)

Compound 133 was prepared as described in Example 1.

MS (ES) 597 (M+H).

Example 135:2-((2-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)-4-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propoxy)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile(Compound 134, formate salt)

Compound 134 was prepared as described in Example 1.

MS (ES) 675 (M+H).

Example 136:2-((2-fluoro-4-(2-hydroxyethoxy)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile(Compound 135)

Compound 135 was prepared as described in Example 1.

MS (ES) 539 (M+H).

Example 137:2-((2-fluoro-4-(2-hydroxypropoxy)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile(Compound 136, formate salt)

Compound 136 was prepared as described in Example 1.

MS (ES) 553 (M+H).

Example 138:2-((2-fluoro-4-(2-hydroxyethoxy-1,1,2,2-d4)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile(Compound 137)

Compound 137 was prepared as described in Example 1.

MS (ES) 543 (M+H).

Example 139:2-(4-((5-fluoro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-2-(1H-tetrazol-1-yl)phenoxy)ethan-1-ol(Compound 138)

Compound 138 was prepared as described in Example 1.

MS (ES) 484 (M+H).

Example 140:2-(4-((5-chloro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-2-(1H-tetrazol-1-yl)phenoxy)ethan-1-ol(Compound 139)

Compound 139 was prepared as described in Example 1.

MS (ES) 501 (M+H).

Example 141:2-((4-(2-hydroxyethoxy)-3-(1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile(Compound 140)

Compound 140 was prepared as described in Example 1.

MS (ES) 491 (M+H).

Example 142:2-(4-((4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-2-(1H-tetrazol-1-yl)phenoxy)ethan-1-ol(Compound 141)

Compound 141 was prepared as described in Example 1.

MS (ES) 466 (M+H).

Example 143:2-((2-fluoro-4-((S)-2-hydroxypropoxy)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile(Compound 142)

Compound 142 was prepared as described in Example 1.

MS (ES) 553 (M+H).

Example 144:2-((2-fluoro-4-((R)-2-hydroxypropoxy)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile(Compound 143, formate salt)

Compound 143 was prepared as described in Example 1.

MS (ES) 553 (M+H).

Example 145:2-((3-cyano-4-(2-hydroxypropoxy)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile(Compound 144, formate salt)

Compound 144 was prepared as described in Example 1.

MS (ES) 462 (M+H).

Example 146:5-((5-fluoro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-2-(2-hydroxypropoxy)benzonitrile(Compound 145, formate salt)

Compound 145 was prepared as described in Example 1.

MS (ES) 455 (M+H).

Example 147:1-(5-((5-chloro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-4-fluoro-2-hydroxyphenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one(Compound 146)

Compound 146 was prepared as described in Example 1.

MS (ES) 504 (M+H).

Example 148:1-(5-((5-fluoro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-4-fluoro-2-hydroxyphenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one(Compound 147)

Compound 147 was prepared as described in Example 1.

MS (ES) 488 (M+H).

Example 149:1-(4-fluoro-5-((5-fluoro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-2-((1-hydroxy-2-methylpropan-2-yl)oxy)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one(Compound 148)

Compound 148 was prepared as described in Example 1.

MS (ES) 560 (M+H).

Example 150:1-(4-fluoro-5-((5-fluoro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-2-((S)-2-hydroxypropoxy)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one(Compound 149)

Compound 149 was prepared as described in Example 1.

MS (ES) 546 (M+H).

Example 151: ethyl2-(4-((5-cyano-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-5-fluoro-2-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenoxy)-2-methylpropanoate(Compound 150)

Compound 150 was prepared as described in Example 1.

MS (ES) 609 (M+H).

Example 152:2-((2-fluoro-4-((1-hydroxy-2-methylpropan-2-yl)oxy)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile(Compound 151)

Compound 151 was prepared as described in Example 1.

MS (ES) 567 (M+H).

Example 153:1-(5-((5-chloro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-4-fluoro-2-((S)-2-hydroxypropoxy)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one(Compound 152)

Compound 152 was prepared as described in Example 1.

MS (ES) 563 (M+H).

Example 154:1-(5-((5-chloro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-4-fluoro-2-((1-hydroxy-2-methylpropan-2-yl)oxy)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one(Compound 153)

Compound 153 was prepared as described in Example 1.

MS (ES) 577 (M+H).

Example 155:1-(4-fluoro-5-((5-fluoro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-2-(2-hydroxy-2-methylpropoxy)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one(Compound 154)

Compound 154 was prepared as described in Example 1.

MS (ES) 560 (M+H).

Example 156:1-(5-((5-chloro-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidin-2-yl)amino)-4-fluoro-2-(2-hydroxy-2-methylpropoxy)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one(Compound 155)

Compound 155 was prepared as described in Example 1.

MS (ES) 577 (M+H).

Example 157:2-((2-fluoro-4-(2-hydroxy-2-methylpropoxy)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)amino)-4-((((1S,9aR)-octahydro-2H-quinolizin-1-yl)methyl)amino)pyrimidine-5-carbonitrile(Compound 156)

Compound 156 was prepared as described in Example 1.

MS (ES) 567 (M+H).

Biological Examples Example 158: PKC Assay

The inhibition of PKC-alpha, PKC-beta, PKC-delta, PKC epsilon andPKC-theta activity is determined via ELISA as follows: NUNC MAXISORP(#436110) or Costar High Binding (#3922) plates are coated with 0.01mg/ml Neutravidin (Pierce #PI-31000) in 1×PBS (100 μL/well) for 18-24hours at 4° C. When ready to be used, plates are washed with 1×PBST andthen blocked with 2% BSA in 1×PBST (100 μL/well) for a minimum of 1 hourat room temperature. The reactions are conducted in a volume of 60μL/well. When ready to begin, the plates are washed with 1×PBST toremove the 2% BSA blocking solution. Reaction solution containing thenecessary buffer components as well as the appropriate concentrations ofATP and peptide substrate is then added to each well (see Table 3).Appropriate concentrations of test compound is then added with thevolume added should taking into consideration the DMSO tolerance of thekinases being about 0.2%. The reaction is then initiated by the additionof kinase the approximate final concentration of which is listed inTable 3 (the concentration may vary depending on the batch to batchvariability in the activity of enzymes). After allowing the reaction tostand at room temperature for 20 minutes, the plates are then washedwith 1×PBST.

TABLE 3 Buffer [ATP] Time Kinase components (uM) [peptide] (uM) (min) 1°and 2° antibodies Notes PKCs 20 mM Hepes 1 μM 1 μM PKC peptide 20 minRabbit pSer PKC 0.15 mg/ml DAG α: ~8 ng/ml pH 7.4 (biotin- substrate Ab(Cell (Sigma #D0138) β: ~16 ng/ml 5 mM MgCl₂ RFARKGSLRQKNV) Signaling#2261); 0.75 mg/ml δ: ~13 ng/ml 0.2 mM CaCl₂ (Invitrogen #P2760)HRP-goat a-rabbit Phosphoserine ϵ: ~13 ng/ml 1 mM DTT (Jackson (Sigma#P6641) θ: ~8 ng/ml 0.05% Chaps Immunoresearch DMSO toler- #111-035-003)ance ~0.2%

After removal of the reaction mixture from the plate and washing with1×PBST, an antibody developing solution containing a 1:10,000 dilutionof the appropriate primary and secondary antibodies (Table 3) in a 0.1%BSA solution in 1×PBST is then added to each well (100 μL/well). This isthen allowed to stand at room temperature for a minimum of 1 hour. Afterthis time, the plates are again washed with 1×PBST. The SuperSignalELISA Pico Chemiluminescent substrate (Pierce #PI-37069) was then added(100 μL/well) and the plate is read on a luminescence plate reader.

Example 159: PKC Assay

Alternatively, the inhibition of PKC activity is measured by monitoringthe production of phosphorylated peptide by fluorescence polarization atdifferent concentrations of the inhibitor. Reactions are carried out in96-well plate format with a total volume of 20 μL containing 20 mMHEPES, pH 7.4, 5 mM MgCl₂, 0.2 mM CaCl₂, 1 mM DTT, 0.02% Brij-35, 0.1mg/ml phosphatidylserine, 0.02 mg/ml dioleoyl-sn-glycerol and 5 μM eachof ATP and the peptide substrate. Compounds are first diluted seriallyin DMSO and then transferred to a solution containing the aboveconcentrations of HEPES, MgCl₂, CaCl₂, DTT, and Brij-35 to yield 5×compound solutions in 2% DMSO, which is then added to the reactionsolution. Reactions are initiated by the addition of PKC at a typicalconcentration as described in Table 4, and then allowed to incubate atroom temperature for 20 minutes. At the end of this time, a combinationof quench (EDTA) and detection (peptide tracer and antibody) reagents isadded using the protocol of Invitrogen P2748. After a 30 minutes periodof incubation, the amount of phosphorylated peptide generated ismeasured by fluorescence polarization (Ex=485 nm, Em=535 nm) using aTecan Polarian instrument.

TABLE 4 Typical enzyme Peptide  SEQ  concen- substrate ID Enzyme sourcetration PKC  RFARKGSLR Seq ID  Upstate  40 theta QKNV No. 1Biotechnologies, ng/ml Temecula, CA,  cat. #14-444 PKC  RFARKGSLRSeq ID  Upstate  50 epsilon QKNV No. 1 Biotechnologies, ng/mlTemecula, CA,  cat. #14-518

Example 160: Calcium Influx

HEK-FLPTREX cells are stably transfected with pcDNA5/FRT/TO+hTRPV4a, ratTRPV1-HA or rTRPA1-HA are grown in Dulbecco's Modified Eagle's Medium(DMEM) containing 10% tetracycline-free fetal bovine serum, hygromycin(50 μg/ml) and blasticidin (10 μg/ml). Cells are treated withtetracycline (0.1 μg/ml, 20 h) to induce TRP expression. DRG fromthoracic and lumbar spinal cord of rats or mice were minced in coldHank's Balanced Salt Solution (HBSS) and incubated for 60 at 37° C. inDMEM containing 1 mg/ml of collagenase type IA and 0.1 mg/ml of DNAsetype IV, pelleted and incubated with 0.25% trypsin for 30 minutes.Neurons are pelleted, suspended in DMEM containing 10% fetal bovineserum, 10% horse serum, 100 U/ml penicillin, 0.1 mg/ml streptomycin, 2mM glutamine, dissociated by gentle trituration until the solutionappears cloudy and homogeneous and plated on glass coverslips coatedwith PolyOnitine/laminin. Neurons are cultured for 3-4 days before theexperiment.

Cells grown on coverslips or on a 96 multiwell plate are incubated inHBSS (pH 7.4) containing Ca2+ and Mg2+, 20 mM HEPES buffer, 0.1% BSA,100 U/ml penicillin, 100 μg/ml streptomycin, with 2.5-5 μM Fura-2AM(Invitrogen) for 20-45 minutes at 37° C. Cells are washed andfluorescence is measured at 340 nm and 380 nm excitation and 510 nmemission in a F-2500 spectrophotometer, or in a Flexstation 3 MicroplateReader III (for the measurement of the calcium in the cell population)or using a Zeiss Axiovert microscope, an ICCD video camera and a videomicroscopy acquisition program (for the measurement of the calciuminflux in the single neurons). Substances are injected directly into thechamber (20 ml into 2 ml, for the spectrophotometer; 20 ml in 200 ml forthe Flexstation, 50 ml in 350 ml in the chamber for the single cells).

Example 161: In Vivo Hyperplasia

Mechanical pain is quantified as the number of times the hind paw iswithdrawn in response to 5 applications of a 0.173 mN von Frey hair.Responses are expressed as a percentage (e.g. 3 withdrawals out of 5 arerecorded as 60%) and mechanical hyperalgesia defined as increase in thepercentage of withdrawal compared to basal measurement. 2) Mechanicalpain is quantified using the ‘up-down paradigm’, determining the 50%response threshold to the von Frey filaments applied to the mid-plantarsurface for 5 s or until a withdrawal response occurred. Von Freyfilaments are in this range of intensities: 1.65, 2.44, 2.83, 3.22,3.61, 3.84, 4.08.

Thermal hyperalgesia is assessed in mice using a plantar test apparatusand quantified as the latency of paw withdrawal to a radiant heat.Thermal hyperalgesia is defined as a decrease in the withdrawal latencycompared to the basal measurement. After measuring basal level mice,under light halothane anesthesia (5%), are injected with testingcompound into the left or right paws (5-10 μl intraplantar injection)and paw withdrawal measurements repeated at different time point. Toassess PAR2 TRPV1, TRPV4 and TRPA1 mediated hyperalgesia andpotentiation of TRPV-mediated responses, mice are treated with PAR2-APfor 15 minutes followed by capsaicin, 4αPDD or HNE. To assess the roleof protein kinases, the antagonists or the corresponding vehicles areinjected 20-30 minutes before the challenge with agonists. The effectsinduced by the different treatments are evaluated within the same ratcomparing the responses recorded in the right paw (receiving for examplesaline, or vehicle) with the responses obtained in the left paw(receiving for example PAR2-AP or 4αPDD).

Formalin induced hyperalgeisa is assessed using 5% solution of formalinadministered by intradermal injection into the dorsal surface of themouse or rat forepaw to induce a painful behavior. Pain is accessed on afour-level scale related to posture: 0, normal posture; 1, with theinjected paw remaining on the ground but not supporting the animal; 2,with the injected paw clearly raised; and 3, with the injected paw beinglicked, nibbled, or shaken. Animals are observed and scored for behaviorat 3 minutes after the injection (defined as initial phase that resultsfrom the direct stimulation of nociceptors), and then at 30-60 minutesafter the injection (defined as second phase that involves a period ofsensitization during which inflammatory phenomena occur). Thenociceptive behavioral score for each 3-minutes interval is calculatedas the weighted average of the number of seconds spent in each behavior.2.5% solution of formalin is administered by intraplantar injection andthermal and mechanical pain measured as described above after 30-60minutes. To assess the role of protein kinases, antagonists or theirvehicles (control) are injected into the right paws 20-30 minutes beforeformalin. Nociceptive behavior will be scored for each rats and comparedto control.

Example 162: IL-2 ELISA, Human Primary T Cell, Anti CD3+CD28+

Compounds 1-156 were tested in a whole cell functional assay for PKCmediated IL-2 production as follows. Human primary T cell isolation andculture: Human primary T cells were prepared as follows. Whole blood wasobtained from a healthy volunteer, mixed 1:1 with PBS, layered on toFicoll Hypaque (Amersham Pharmacia Biotech, Piscataway, N.J., Catalog#17-1440-03) in 2:1 blood/PBS:ficoll ratio and centrifuged for 30minutes at 4° C. at 1750 rpm. The cells at the serum: ficoll interfacewere recovered and washed twice with 5 volumes of PBS. These freshlyisolated human peripheral blood mononuclear cells were cultured inYssel's medium containing 40 U/ml IL2 in a flask pre-coated with 1 μg/mlaCD3 and 5 μg/ml aCD28 (Anti-Human CD3, BD Pharmingen Catalog #555336,Anti-Human CD28, Beckman Coulter Catalog #IM1376). The cells werestimulated for 3-4 days, then transferred to a fresh flask andmaintained in RPMI (RPMI-1640 with L-Glutamine; Mediatech, Inc., HerndonVa., cat. #10-040-CM) with 10% FBS and 40 U/ml IL-2. The primary T-cellswere then washed twice with PBS to remove the IL-2.

Primary T cell stimulation and IL2 ELISA: Human primary T cells (100,000cells per well) were pre-incubated with or without test compound inYssel's medium for 1 hour at 37° C. Cells were then stimulated bytransferring them to round-bottom 96-well plates pre-coated with 1 μg/mlaCD3 and 5 μg/ml αCD28. For counter assay, cells were instead stimulatedby adding 8× stock solutions of PMA and ionomycin in Yssels (for finalconcentrations of 0.5 ng/ml PMA and 0.1 uM ionomycin, both fromCalbiochem). Cells were incubated at 37° C. for 24 hours before 100 μLsupernatants were harvested for quantification of IL-2 by ELISA usingHuman IL-2 Duoset ELISA Kit from R and D Systems, Cat. # DY202E.Compounds 1-156 blocked IL-2 production with an IC₅₀ of less than 30micromolar.

IC₅₀ data (micromolar) is shown in Table 5 below.

TABLE 5 IL2 ELISA, Human primary T cell, anti- Compound CD3 + CD28, 8 pt(μM) 1 0.1069 2 0.3718 3 1.68 4 0.1419 5 0.1201 6 0.0889 7 0.4279 80.1057 9 0.1947 10 0.5944 11 1.079 12 0.8891 13 4.48 14 0.2011 15 10.6516 0.7025 17 0.4052 18 0.1265 19 0.5536 20 1.075 21 0.7019 22 0.6972 230.0663 24 3.45 25 0.8529 26 0.1694 27 0.6518 28 1.815 29 1.803 30 0.671631 0.3592 32 0.1587 33 0.1173 34 0.6696 35 0.0542 36 0.1124 37 0.0872 380.1264 39 0.4177 40 0.2666 41 0.0723 42 0.3481 43 0.4122 44 1.18 450.224 46 1.12 47 0.6487 48 3.815 49 0.8967 50 1.996 51 0.5315 52 0.442353 2.526 54 1.098 55 0.6073 56 3.797 57 3.586 58 18.62 59 0.16 60 1.35661 1.979 62 1.872 63 1.161 64 0.4593 65 0.0728 66 1.479 67 1.077 68 0.9569 0.265 70 1.53 71 3.747 72 1.271 73 3.269 74 2.194 75 2.912 76 6.44877 2.418 78 2.241 79 5.354 80 2.484 81 1.308 82 1.306 83 3.872 84 15.485 3.314 86 11.04 87 8.257 88 12.73 89 14.58 90 9.82 91 7.943 92 9.45793 3.922 94 2.573 95 1.74 96 4.981 97 5.41 98 0.0774 99 0.0509 100 4.214101 10.69 102 12.64 103 26.55 104 26.8 105 11.75 106 21.47 107 17.07 10841.2 109 6.576 110 10.71 111 12.5 112 21.72 113 0.018 114 0.0365 1150.0225 116 0.0074 117 0.0117 118 0.076 119 0.0357 120 0.0093 121 0.1414122 0.0206 123 0.0418 124 0.0031 125 1.784 126 1.602 127 0.8239 1281.937 129 1.336 130 0.4443 131 1.305 132 1.238 133 0.9923 134 0.9084 1355008 136 0.1761 137 9999 138 0.0493 139 0.0175 140 0.0276 141 3.549 1420.0662 143 0.1468 144 12.39 145 4.628 146 1.976 147 5.06 148 1.592 1490.2655 150 1.139 151 0.3055 152 0.0898 153 0.8319 154 0.1877 155 0.1358156 0.0276

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A method of inhibiting a protein kinase C (PKC)activity comprising: contacting a PKC with a compound of formula (I):

wherein R¹¹ is selected from hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy,amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen,acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkylthioalkylene, substituted alkylthioalkylene, and SF₅;Y¹ and Y² are independently selected from hydrogen and alkyl; and Ar¹ isselected from aryl, substituted aryl, heteroaryl, and substitutedheteroaryl; or a pharmaceutically acceptable salt or stereoisomerthereof, wherein the contacting results in inhibition of the PKCactivity.
 2. A method for inhibiting IL-2 production in T cells, themethod comprising contacting T cells with a compound of formula (I):

wherein: R¹¹ is selected from hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy,amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen,acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkylthioalkylene, substituted alkylthioalkylene, and SF₅;Y¹ and Y² are independently selected from hydrogen and alkyl; and Ar¹ isselected from aryl, substituted aryl, heteroaryl, and substitutedheteroaryl; or a pharmaceutically acceptable salt or stereoisomerthereof.
 3. A method for treating an inflammatory disease or disordermediated or sustained through a PKC activity, the method comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound of formula (I):

wherein: R¹¹ is selected from hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy,amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen,acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkylthioalkylene, substituted alkylthioalkylene, and SF₅;Y¹ and Y² are independently selected from hydrogen and alkyl; and Ar¹ isselected from aryl, substituted aryl, heteroaryl, and substitutedheteroaryl; or a pharmaceutically acceptable salt or stereoisomerthereof.
 4. A method for treating an autoimmune disease or disordermediated or sustained through a PKC activity, the method comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound of formula (I):

wherein: R¹¹ is selected from hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy,amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen,acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkylthioalkylene, substituted alkylthioalkylene, and SF₅;Y¹ and Y² are independently selected from hydrogen and alkyl; and Ar¹ isselected from aryl, substituted aryl, heteroaryl, and substitutedheteroaryl; or a pharmaceutically acceptable salt or stereoisomerthereof.
 5. A method for treating an ocular disease or disorderinvolving inflammatory and/or neovascular events mediated or sustainedthrough a PKC activity, the method comprising administering to a subjectin need thereof a therapeutically effective amount of a compound offormula (I):

wherein: R¹¹ is selected from hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy,amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen,acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkylthioalkylene, substituted alkylthioalkylene, and SF₅;Y¹ and Y² are independently selected from hydrogen and alkyl; and Ar¹ isselected from aryl, substituted aryl, heteroaryl, and substitutedheteroaryl; or a pharmaceutically acceptable salt or stereoisomerthereof.